Muscarinic agonists

ABSTRACT

Compounds and methods are provided for the treatment of disease conditions in which modification of cholinergic, especially muscarinic m1, m4, or both m1 and m4, receptor activity has a beneficial effect. In the method, an effective amount of a compound is administered to a patient in need of such treatment.

This application is a divisional of U.S. patent application Ser. No.09/844,685, entitled “MUSCARINIC AGONISTS,” filed Apr. 27, 2001, nowU.S. Pat. No. 6,627,645, issued Sep. 30, 2003, by Andersson, et al.,which in turn claims priority to U.S. Provisional Patent ApplicationSer. No. 60/200,791, filed Apr. 28, 2000, all of which are incorporatedby reference herein in their entirety, including any drawings.

FIELD OF THE INVENTION

The present invention relates to compounds that affect cholinergicreceptors, especially muscarinic receptors. The present inventionprovides compounds that are agonists of cholinergic receptors includingmuscarinic receptors, especially the m1 and m4 subtype of muscarinicreceptors. The invention also provides methods of using the providedcompounds for modulating conditions associated with cholinergicreceptors, especially for treating or alleviating disease conditionsassociated with muscarinic receptors, e.g., m1 or m4 subtypes ofreceptors.

BACKGROUND OF THE INVENTION

Muscarinic cholinergic receptors mediate the actions of theneurotransmitter acetylcholine in the central and peripheral nervoussystems, gastrointestinal system, heart, endocrine glands, lungs, andother tissues. Muscarinic receptors play a central role in the centralnervous system for higher cognitive functions, as well as in theperipheral parasympathetic nervous system. Five distinct muscarinicreceptor subtypes have been identified, m1–m5. The m1 subtype is thepredominant subtype found in the cerebral cortex and is believed to beinvolved in the control of cognitive functions; m2 is the predominantsubtype found in heart and is believed to be involved in the control ofheart rate; m3 is believed to be involved in gastrointestinal andurinary tract stimulation as well as sweating and salivation; m4 ispresent in brain and may be involved in locomotion; and m5, present inbrain, may be involved in certain functions of the central nervoussystem associated with the dopaminergic system.

Conditions associated with cognitive impairment, such as Alzheimer'sdisease, are accompanied by loss of acetylcholine in the brain. This isbelieved to be the result of degeneration of cholinergic neurons in thebasal forebrain, which innervate areas of the association cortex, andhippocampus, which is involved in higher processes.

Efforts to increase acetylcholine levels have focused on increasinglevels of choline, the precursor for acetylcholine synthesis, and onblocking acetylcholine esterase (AChE), the enzyme that metabolizesacetylcholine. Administration of choline or phosphatidylcholine has notbeen very successful. AChE inhibitors have shown some therapeuticefficacy, but may cause cholinergic side effects due to peripheralacetylcholine stimulation, including abdominal cramps, nausea, vomiting,diarrhea, anorexia, weight loss, myopathy and depression.Gastrointestinal side effects have been observed in about a third of thepatients treated. In addition, some ACHE inhibitors, such as tacrine,have also been found to cause significant hepatotoxicity, with elevatedliver transaminases observed in about 30% of patients. The adverseeffects of AChE inhibitors have limited their clinical utility.

Known m1 muscarinic agonists such as arecoline have also been found tobe weak agonists of m2 as well as m3 subtype and are not very effectivein treating cognitive impairment, most likely because of dose-limitingside effects.

There is a need for compounds that increase acetylcholine signaling oreffect in the brain. Specifically there is a need for muscarinicagonists that are active at various muscarinic receptor subtypes in thecentral and peripheral nervous system. Furthermore, there is a need formore highly selective muscarinic agonists, such as m1- or m4-selectiveagents, both as pharmacological tools and as therapeutic agents.

SUMMARY OF THE INVENTION

The present invention provides compounds that affect cholinergic,especially muscarinic, receptors that have agonist activity at the m1 orm4 subtype of muscarinic receptors, or both. The compounds of theinvention are of the general formula (I):

wherein:

-   -   Z₁ is CR₁ or N, Z₂ is CR₂ or N, Z₃ is CR₃ or N, and Z₄ is CR₄ or        N, where no more than two of Z₁, Z₂, Z₃ and Z₄ are N;    -   W₁ is O, S, or NR₅, one of W₂ and W₃ is N or CR₆, and the other        of W₂ and W₃ is CG; W₁ is NG, W₂ is CR₅ or N, and W₃ is CR₆ or        N; or W₁ and W₃ are N, and W₂ is NG;    -   G is of formula (II):

-   -   Y is O, S, CHOH, —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, —(O)CO—,        —NR₇—, —CH═N—, or absent;    -   p is 1, 2, 3, 4 or 5;    -   Z is CR₈R₉ or absent;    -   each t is 1, 2, or 3;    -   each R₁, R₂, R₃, and R₄, independently, is H, amino, hydroxyl,        halo, or straight- or branched-chain C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ heteroalkyl, C₁₋₆ haloalkyl, —CN, —CF₃,        —OR₁₁, —COR₁₁, —NO₂, —SR₁₁, —NHC(O)R₁₁, —C(O)NR₁₂R₁₃, —NR₁₂R₁₃,        —NR₁₁C(O)NR₁₂R₁₃, —SO₂NR₁₂R₁₃, —OC(O)R₁₁, —O(CH₂)_(q)NR₁₂R₁₃, or        —(CH₂)_(q)NR₁₂R₁₃, where q is an integer from 2 to 6, or R₁ and        R₂ together form —NH—N═N— or R₃ and R₄ together form —NH—N═N—;    -   each R₅, R₆, and R₇, independently, is H, C₁₋₆ alkyl; formyl;        C₃₋₆ cycloalkyl; C₅₋₆ aryl, optionally substituted with halo or        C₁₋₆ alkyl; or C₅₋₆ heteroaryl, optionally substituted with halo        or C₁₋₆ alkyl;    -   each R₈ and R₉, independently, is H or straight- or        branched-chain C₁₋₈ alkyl;    -   R₁₀ is straight- or branched-chain C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, C₁₋₈ alkylidene, C₁₋₈ alkoxy, C₁₋₈ heteroalkyl,        C₁₋₈ aminoalkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxycarbonyl, C₁₋₈        hydroxyalkoxy, C₁₋₈ hydroxyalkyl, —SH, C₁₋₈ alkylthio,        —O—CH₂—C₅₋₆ aryl, —C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or        halo, C₅₋₆ aryl, C₅₋₆ cycloalkyl, C₅₋₆ heteroaryl, C₅₋₆        heterocycloalkyl, —NR₁₂R₁₃, —C(O)NR₁₂R₁₃, —NR₁₁C(O)NR₁₂R₁₃,        —CR₁₁R₁₂R₁₃, —OC(O)R₁₁, —(O)(CH₂)_(S)NR₁₂R₁₃ or        —(CH₂)_(S)NR₁₂R₁₃, s being an integer from 2 to 8;    -   R₁₀′ is H, straight- or branched-chain C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, C₁₋₈ alkylidene, C₁₋₈ alkoxy, C₁₋₈ heteroalkyl,        C₁₋₈ aminoalkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxycarbonyl, C₁₋₈        hydroxyalkoxy, C₁₋₈ hydroxyalkyl, or C₁₋₈ alkylthio;    -   each R₁₁, independently, is H, straight- or branched-chain C₁₋₈        alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₂₋₈ heteroalkyl, C₂₋₈        aminoalkyl, C₂₋₈ haloalkyl, C₁₋₈ alkoxycarbonyl, C₂₋₈        hydroxyalkyl, —C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or        halo, C₅₋₆ aryl, C₅₋₆ heteroaryl, C₅₋₆ Cycloalkyl, C₅₋₆        heterocycloalkyl, —C(O)NR₁₂R₁₃, —CR₅R₁₂R₁₃, —(CH₂)_(t)NR₁₂R₁₃, t        is an integer from 2 to 8; and    -   each R₁₂ and R₁₃, independently, is H, C₁₋₆ alkyl; C₃₋₆        cycloalkyl; C₅₋₆ aryl, optionally substituted with halo or C₁₋₆        alkyl; or C₅₋₆ heteroaryl, optionally substituted with halo or        C₁₋₆ alkyl; or R₁₂ and R₁₃ together form a cyclic structure;    -   or a pharmaceutically acceptable salt, ester or prodrug thereof.

The present invention further provides pharmaceutical compositionsincluding an effective amount of a compound of formula (I) orpharmaceutically acceptable salts, esters, or prodrugs thereof.

Also provided are methods of increasing an activity of a cholinergicreceptor comprising contacting the cholinergic receptor or a systemcontaining the cholinergic receptor with an effective amount of acompound of formula (I), as well as kits for performing the same.Preferably, the receptor is a muscarinic receptor of the m1 or m4subtype. The receptor may be located in the central nervous system,peripheral nervous system, gastrointestinal system, heart, endocrineglands, or lungs; and the receptor may be a truncated, mutated, ormodified cholinergic receptor.

Furthermore, the present invention relates to a method of activating acholinergic receptor comprising contacting the cholinergic receptor or asystem containing the cholinergic receptor with an effective amount ofat least one compound of formula (I), as well as kits for performing themethod. In a preferred embodiment, the compound is selective for the m1or m4 muscarinic receptor subtype, or both. In another preferredembodiment, the compound has little or substantially no effect on m2 orm3 activity.

Another aspect of the present invention relates to a method of treatinga disease condition associated with a cholinergic receptor comprisingadministering to a subject in need of such treatment an effective amountof at least one of the compounds of the invention. Kits for performingthe method are also provided. The disease conditions that are treatedinclude, but are not limited to conditions of cognitive dysfunction,forgetfulness, confusion, memory loss, attention deficits, deficits invisual perception, depression, pain, sleep disorders, and psychosis. Thedisease conditions also include, but are not limited to diseases ofAlzheimer's disease, Parkinson's disease, Huntington's chorea,Friederich's ataxia, Gilles de la Tourette's Syndrome, Down Syndrome,Pick disease, dementia pugilistica, clinical depression, age-relatedcognitive decline, attention-deficit disorder, and sudden infant deathsyndrome.

Further provided are methods of treating the symptoms of a disease orcondition associated with reduced levels of acetylcholine comprisingadministering an effective amount of at least one compound of theinvention.

In yet another embodiment, the present invention provides a method oftreating Alzheimer's disease. The method comprises administering to asubject in need of such treatment an effective amount of at least onecompound of the invention.

In still another embodiment, the present invention provides a method oftreating glaucoma. The method comprises administering an effectiveamount of at least one compound of the invention.

Another aspect of the present invention is a method for identifying agenetic polymorphism predisposing a subject to being responsive to acompound of the invention. The method comprises administering to asubject a therapeutically effective amount of the compound; measuringthe response of said subject to the compound, thereby identifying aresponsive subject having an ameliorated disease condition associatedwith a cholinergic receptor; and identifying a genetic polymorphism inthe responsive subject, wherein the genetic polymorphism predisposes asubject to being responsive to the compound.

The present invention also features a method for identifying a subjectsuitable for treatment with a compound of the invention, and kits foridentifying the same. The method comprises detecting the presence of apolymorphism in a subject wherein the polymorphism predisposes thesubject to being responsive to the compound, and wherein the presence ofthe polymorphism indicates that the subject is suitable for treatmentwith the compound.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

For the purpose of the current disclosure, the following definitionsshall in their entireties be used to define technical terms and todefine the scope of the composition of matter for which protection issought in the claims.

A “receptor” is intended to include any molecule present inside or onthe surface of a cell that may affect cellular physiology when it isinhibited or stimulated by a ligand. Typically, a receptor comprises anextracellular domain with ligand-binding properties, a transmembranedomain that anchors the receptor in the cell membrane, and a cytoplasmicdomain that generates a cellular signal in response to ligand binding(“signal transduction”). A receptor also includes any molecule havingthe characteristic structure of a receptor, but with no identifiableligand. In addition, a receptor includes a truncated, modified, mutatedreceptor, or any molecule comprising partial or all of the sequences ofa receptor.

“Ligand” is intended to include any substance that interacts with areceptor.

“Agonist” is defined as a compound that increases the activity of areceptor when it interacts with the receptor.

The “m1 receptor” is defined as a receptor having an activitycorresponding to the activity of the m1 muscarinic receptor subtypecharacterized through molecular cloning and pharmacology.

“Selective” or “selectivity” is defined as a compound's ability togenerate a desired response from a particular receptor type, subtype,class or subclass while generating less or little response from otherreceptor types. “Selective” or “selectivity” of an m1 or m4 muscarinicagonist compound means a compound's ability to increase the activity ofthe m1 or m4 muscarinic receptor, respectively, while causing little orno increase in the activity of other subtypes including m3 and m5subtypes, and preferably the m2 subtype. Compounds of the presentsinvention may also show selectivity toward both m1 and m4 receptors,i.e. increase the activity of both the m1 and m4 muscarinic receptors,while causing little or no increase in the activity of other subtypesincluding the m3 and m5 subtypes, and preferably the m2 subtype.

The term “subject” refers to an animal, preferably a mammal or a human,who is the object of treatment, observation or experiment.

As used herein, “coadministration” of pharmacologically active compoundsrefers to the delivery of two or more separate chemical entities,whether in vitro or in vivo. Coadministration means the simultaneousdelivery of separate agents; the simultaneous delivery of a mixture ofagents; as well as the delivery of one agent followed by delivery of asecond agent or additional agents. Agents that are coadministered aretypically intended to work in conjunction with each other.

The term “an effective amount” as used herein means an amount of activecompound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician,which includes alleviation or palliation of the symptoms of the diseasebeing treated.

“Alkyl” means a straight or branched-chain alkane group with 1–6 carbonatoms in the chain, for instance methyl, ethyl, propyl, isopropyl,n-butyl, sec-butyl, tert-butyl, etc. The term “heteroalkyl” is intendedto indicate an alkane group containing 1 or 2 heteroatoms selected fromO, S or N.

“Alkenyl” means a straight or branched-chain alkene group with 2–6carbon atoms in the chain; the term “alkynyl” is intended to indicate astraight or branched-chain alkyne group with 2–6 carbon atoms in thechain.

The terms “aryl” and “cycloalkyl” preferably refer to mono- and bicyclicring structures comprising 5 to 12 carbon atoms, more preferablymonocyclic rings comprising 5 to 6 carbon atoms. Where such ringscomprise one or more heteroatoms, selected from N, S and O, (i.e.,heterocyclic, or heteroaryl rings) such rings comprise a total of 5 to12 atoms, more preferably 5 to 6 atoms. Heterocyclic rings include, butare not limited to, furyl, pyrrolyl, pyrazolyl, thienyl, imidazolyl,indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzoimidazolyl,benzothiazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridyl,piperidinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl,morpholinyl, oxadiazolyl, thiadiazolyl, imidazolinyl, imidazolidinyl andthe like. The ring may be substituted by one or more of the groupsincluded in the definition of R₂ above. It is understood that thesubstituents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆heteroalkyl, C₁₋₆ aminoalkyl, C₁₋₆ haloalkyl or C₁₋₆ alkoxycarbonyl may,if present, be substituted by one or more of hydroxyl, C₁₋₄ alkoxy,halogen, cyano, amino or nitro.

As used herein, the term “halogen” or “halo” includes chlorine,fluorine, which are preferred, and iodine and bromine.

The present invention provides compounds that are agonists ofcholinergic receptors including muscarinic receptors. Especially, thepresent invention provides compounds that are selective for the m1 or m4muscarinic receptor subtype, or both. The compounds provided by thepresent invention have therapeutic effect and can be used to treatdisease conditions associated with cholinergic receptors, e.g.,cognitive impairment in Alzheimer's disease, glaucoma, pain, orschizophrenia.

According to one embodiment, the present invention provides compounds offormula (I)

wherein:

-   -   Z₁ is CR₁ or N, Z₂ is CR₂ or N, Z₃ is CR₃ or N, and Z₄ is CR₄ or        N, no more than two of Z₁, Z₂, Z₃ and Z₄ being N;    -   W₁ is O, S, or NR₅, one of W₂ and W₃ is N or CR₆ and the other        of W₂ and W₃ is CG; W₁ is NG, W₂ is CR₅ or N, and W₃ is CR₆ or        N; or W₁ is N, W₂ is NG and W₃ is N;    -   G is of formula (II):

-   -   Y is O, S, CHOH, —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, —(O)CO—,        —NR₇—, —CH═N—, or absent;    -   p is 1, 2, 3, 4 or 5;    -   Z is CR₈R₉ or absent;    -   each t is 1, 2, or 3;    -   each R₁, R₂, R₃, and R₄, independently, is H, amino, hydroxyl,        halo, or straight- or branched-chain C₁alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ heteroalkyl, C₁₋₆ haloalkyl, —CN, —CF₃, —OR₁₁,        —COR₁₁, —NO₂, —SR₁₁, —NHC(O)R₁₁, —C(O)NR₁₂R₁₃, —NR₁₂R₁₃,        —NR₁₁C(O)NR₁₂R₁₃, —SO₂NR₁₂R₁₃, —OC(O)R₁₁, —O(CH₂)_(q)NR₁₂R₁₃, or        —(CH₂)_(q)NR₁₂R₁₃, where q is an integer from 2 to 6, or R₁ and        R₂ together form —NH—N═N— or R₃ and R₄ together form —NH—N═N—;    -   each R₅, R₆, and R₇, independently, is H, C₁₋₆ alkyl; formyl;        C₃₋₆ cycloalkyl; C₅₋₆ aryl, optionally substituted with halo or        C₁₋₆ alkyl; or C₅₋₆ heteroaryl, optionally substituted with halo        or C₁₋₆ alkyl;    -   each R₈ and R₉, independently, is H or straight- or        branched-chain C₁₋₈ alkyl;    -   R₁₀ is straight- or branched-chain C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, C₁₋₈ alkylidene, C₁₋₈ alkoxy, C₁₋₈ heteroalkyl,        C₁₋₈ aminoalkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxycarbonyl, C₁₋₈        hydroxyalkoxy, C₁₋₈ hydroxyalkyl, —SH, C₁₋₈ alkylthio,        —O—CH₂—C₅₋₆ aryl, —C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or        halo, C₅₋₆ aryl, C₅₋₆ cycloalkyl, C₅₋₆ heteroaryl, C₅₋₆        heterocycloalkyl, —NR₁₂R₁₃, —C(O)NR₁₂R₁₃, —NR₁₁C(O)NR₁₂R₁₃,        —CR₁₁R₁₂R₁₃, —OC(O)R₁₁, —(O)(CH₂)_(S)NR₁₂R₁₃ or        —(CH₂)_(S)NR₁₂R₁₃, s being an integer from 2 to 8;    -   R₁₀′ is H, straight- or branched-chain C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, C₁₋₈ alkylidene, C₁₋₈ alkoxy, C₁₋₈ heteroalkyl,        C₁₋₈ aminoalkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxycarbonyl, C₁₋₈        hydroxyalkoxy, C₁₋₈ hydroxyalkyl, or C₁₋₈ alkylthio;    -   each R₁₁, independently, is H, straight- or branched-chain C₁₋₈        alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₂₋₈ heteroalkyl, C₂₋₈        aminoalkyl, C₂₋₈ haloalkyl, C₁₋₈ alkoxycarbonyl, C₂₋₈        hydroxyalkyl, —C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or        halo, C₅₋₆ aryl, C₅₋₆ heteroaryl, C₅₋₆ cycloalkyl, C₅₋₆        heterocycloalkyl, —C(O)NR₁₂R₁₃, —CR₅R₁₂R₁₃, —(CH₂)_(t)NR₁₂R₁₃, t        is an integer from 2 to 8; and    -   each R₁₂ and R₁₃, independently, is H, C₁₋₆ alkyl; C₃₋₆        cycloalkyl; C₅₋₆ aryl, optionally substituted with halo or C₁₋₆        alkyl; or C₅₋₆ heteroaryl, optionally substituted with halo or        C₁₋₆ alkyl; or R₁₂ and R₁₃ together form a cyclic structure;    -   or a pharmaceutically acceptable salt, ester or prodrug thereof.

According to a preferred series of embodiments, t is 2 and R₁₀′ is H.

According to one preferred series of embodiments Y is —C(O)—, —NHC(O)—,S, O, —OC(O)— or absent. In another, R₁₀ is alkyl, and where Z₁ is CR₁or N, Z₂ is CR₂, Z₃ is CR₃ or N, and Z₄ is CR₄. In one embodiment, p is2. In another, R₅ is H or C₁₋₆ alkyl.

In one embodiment each R₁, R₂, R₃, and R₄, independently, is H, halo,—NO₂, or straight- or branched-chain C₁₋₆ alkyl, or R₁ and R₂ togetherform —NH—N═N— or R₃ and R₄ together form —NH—N═N—.

Particular embodiments of the invention include:

-   -   3-[3-(4-methoxypiperidine)-1-yl-propyl]-1H-indole;    -   3-[3-(4-ethoxypiperidine)-1-yl-propyl]-1H-indole;    -   3-[3-(4-propoxypiperidine)-1-yl-propyl]-1H-indole;    -   3-[3-(4-butoxypiperidine)-1-yl-propyl]-1H-indole;    -   3-[3-(4-methoxymethylpiperidine)-1-yl-propyl]-1H-indole;    -   3-[3-(4-ethoxymethylpiperidine)-1-yl-propyl]-1H-indole;    -   3-[3-(4-propoxymethylpiperidine)-1-yl-propyl]-1H-indole;    -   3-[3-(4-methylpiperidine)-1-yl-propyl]-1H-indole;    -   3-[3-(4-ethylpiperidine)-1-yl-propyl]-1H-indole;    -   3-[3-(4-n-propylpiperidine)-1-yl-propyl]-1H-indole;    -   3-[3-(4-n-butylpiperidine)-1-yl-propyl]-1H-indole;    -   3-[2-(4-methoxypiperidine)-1-yl-ethyl]-1H-indole;    -   3-[2-(4-ethoxypiperidine)-1-yl-ethyl]-1H-indole;    -   3-[2-(4-propoxypiperidine)-1-yl-ethyl]-1H-indole;    -   3-[2-(4-butoxypiperidine)-1-yl-ethyl]-1H-indole;    -   3-[2-(4-methoxymethylpiperidine)-1-yl-ethyl]-1H-indole;    -   3-[2-(4-ethoxymethylpiperidine)-1-yl-ethyl]-1H-indole;    -   3-[2-(4-propoxymethylpiperidine)-1-yl-ethyl]-1H-indole;    -   3-[2-(4-methylpiperidine)-1-yl-ethyl]-1H-indole;    -   3-[2-(4-ethylpiperidine)-1-yl-ethyl]-1H-indole;    -   3-[2-(4-n-propylpiperidine)-1-yl-ethyl]-1H-indole;    -   3-[2-(4-n-butylpiperidine)-1-yl-ethyl]-1H-indole;    -   3-[2-(4-methoxypiperidine)-1-yl-ethyl]-benzo[d]isoxazole;    -   3-[2-(4-butoxypiperidine)-1-yl-ethyl]-benzo[d]isoxazole;    -   3-[3-(4-methoxypiperidine)-1-yl-propyl]-benzo[d]isoxazole;    -   3-[3-(4-butoxypiperidine)-1-yl-propyl]-benzo[d]isoxazole;    -   3-[4-(4-methoxypiperidine)-1-yl-butyl]-benzo[d]isoxazole;    -   3-[4-(4-butoxypiperidine)-1-yl-butyl]-benzo[d]isoxazole;    -   1-[3-(4-methoxypiperidine)-1-yl-propyl]-1H-indole;    -   1-[3-(4-ethoxypiperidine)-1-yl-propyl]-1H-indole;    -   1-[3-(4-propoxypiperidine)-1-yl-propyl]-1H-indole;    -   1-[3-(4-butoxypiperidine)-1-yl-propyl]-1H-indole;    -   1-[3-(4-methoxymethylpiperidine)-1-yl-propyl]-1H-indole;    -   1-[3-(4-ethoxymethylpiperidine)-1-yl-propyl]-1H-indole;    -   1-[3-(4-propoxymethylpiperidine)-1-yl-propyl]-1H-indole;    -   1-[3-(4-methylpiperidine)-1-yl-propyl]-1H-indole;    -   1-[3-(4-ethylpiperidine)-1-yl-propyl]-1H-indole;    -   1-[3-(4-n-propylpiperidine)-1-yl-propyl]-1H-indole;    -   1-[3-(4-n-butylpiperidine)-1-yl-propyl]-1H-indole;    -   1-[2-(4-methoxypiperidine)-1-yl-ethyl]-1H-indole;    -   1-[2-(4-ethoxypiperidine)-1-yl-ethyl]-1H-indole;    -   1-[2-(4-propoxypiperidine)-1-yl-ethyl]-1H-indole;    -   1-[2-(4-butoxypiperidine)-1-yl-ethyl]-1H-indole;    -   1-[2-(4-methoxymethylpiperidine)-1-yl-ethyl]-1H-indole;    -   1-[2-(4-ethoxymethylpiperidine)-1-yl-ethyl]-1H-indole;    -   1-[2-(4-propoxymethylpiperidine)-1-yl-ethyl]-1H-indole;    -   1-[2-(4-methylpiperidine)-1-yl-ethyl]-1H-indole;    -   1-[2-(4-ethylpiperidine)-1-yl-ethyl]-1H-indole;    -   1-[2-(4-n-propylpiperidine)-1-yl-ethyl]-1H-indole;    -   1-[2-(4-n-butylpiperidine)-1-yl-ethyl]-1H-indole;    -   1-[3-(4-methoxypiperidine)-1-yl-propyl]-1H-benzotriazole;    -   1-[3-(4-ethoxypiperidine)-1-yl-propyl]-1H-benzotriazole;    -   1-[3-(4-propoxypiperidine)-1-yl-propyl]-1H-benzotriazole;    -   1-[3-(4-butoxypiperidine)-1-yl-propyl]-1H-benzotriazole;    -   1-[3-(4-methoxymethylpiperidine)-1-yl-propyl]-1H-benzotriazole;    -   1-[3-(4-ethoxymethylpiperidine)-1-yl-propyl]-1H-benzotriazole;    -   1-[3-(4-propoxymethylpiperidine)-1-yl-propyl]-1H-benzotriazole;    -   1-[3-(4-methylpiperidine)-1-yl-propyl]-1H-benzotriazole;    -   1-[3-(4-ethylpiperidine)-1-yl-propyl]-1H-benzotriazole;    -   1-[3-(4-n-propylpiperidine)-1-yl-propyl]-1H-benzotriazole;    -   1-[3-(4-n-butylpiperidine)-1-yl-propyl]-1H-benzotriazole;    -   1-[2-(4-methoxypiperidine)-1-yl-ethyl]-1H-benzotriazole;    -   1-[2-(4-ethoxypiperidine)-1-yl-ethyl]-1H-benzotriazole;    -   1-[2-(4-propoxypiperidine)-1-yl-ethyl]-1H-benzotriazole;    -   1-[2-(4-butoxypiperidine)-1-yl-ethyl]-1H-benzotriazole;    -   1-[2-(4-methoxymethylpiperidine)-1-yl-ethyl]-1H-benzotriazole;    -   1-[2-(4-ethoxymethylpiperidine)-1-yl-ethyl]-1H-benzotriazole;    -   1-[2-(4-propoxymethylpiperidine)-1-yl-ethyl]-1H-benzotriazole;    -   1-[2-(4-methylpiperidine)-1-yl-ethyl]-1H-benzotriazole;    -   1-[2-(4-ethylpiperidine)-1-yl-ethyl]-1H-benzotriazole;    -   1-[2-(4-n-propylpiperidine)-1-yl-ethyl]-1H-benzotriazole;    -   1-[2-(4-n-butylpiperidine)-1-yl-ethyl]-1H-benzotriazole;    -   1-[4-(4-methoxypiperidine)-1-yl-butyl]-1H-benzotriazole;    -   1-[4-(4-ethoxypiperidine)-1-yl-butyl]-1H-benzotriazole;    -   1-[4-(4-propoxypiperidine)-1-yl-butyl]-1H-benzotriazole;    -   1-[4-(4-butoxypiperidine)-1-yl-butyl]-1H-benzotriazole;    -   1-[4-(4-methoxymethylpiperidine)-1-yl-butyl]-1H-benzotriazole;    -   1-[4-(4-ethoxymethylpiperidine)-1-yl-butyl]-1H-benzotriazole;    -   1-[4-(4-propoxymethylpiperidine)-1-yl-butyl]-1H-benzotriazole;    -   1-[4-(4-methylpiperidine)-1-yl-butyl]-1H-benzotriazole;    -   1-[4-(4-ethylpiperidine)-1-yl-butyl]-1H-benzotriazole;    -   1-[4-(4-n-propylpiperidine)-1-yl-butyl]-1H-benzotriazole;    -   1-[4-(4-n-butylpiperidine)-1-yl-butyl]-1H-benzotriazole;    -   2-[4-(4-methylpiperidine)-1-yl-butyl]-1H-benzotriazole;    -   2-[4-(4-ethylpiperidine)-1-yl-butyl]-1H-benzotriazole;    -   2-[4-(4-n-propylpiperidine)-1-yl-butyl]-1H-benzotriazole;    -   2-[4-(4-n-butylpiperidine)-1-yl-butyl]-1H-benzotriazole;    -   2-[3-(4-methylpiperidine)-1-yl-propyl]-1H-benzoimidazole;    -   2-[3-(4-ethylpiperidine)-1-yl-propyl]-1H-benzoimidazole;    -   2-[3-(4-n-propylpiperidine)-1-yl-propyl]-1H-benzoimidazole;    -   2-[3-(4-n-butylpiperidine)-1-yl-propyl]-1H-benzoimidazole;    -   2-[2-(4-methylpiperidine)-1-yl-ethyl]-1H-benzoimidazole;    -   2-[2-(4-ethylpiperidine)-1-yl-ethyl]1H-benzoimidazole;    -   2-[2-(4-n-propylpiperidine)-1-yl-ethyl]-1H-benzoimidazole;    -   2-[2-(4-n-butylpiperidine)-1-yl-ethyl]-1H-benzoimidazole;    -   1-(1H-benzoimidazol-2-yl)-4-(4-ethylpiperidine)-butanone;    -   1-(1H-benzoimidazol-2-yl)-4-(4-ethylpiperidine)-butanone;    -   1-(1H-benzoimidazol-2-yl)-4-(4-n-propylpiperidine)-butanone;    -   1-(1H-benzoimidazol-2-yl)-4-(4-n-butylpiperidine)-butanone;    -   1-(1H-benzoimidazol-2-yl)-3-(4-methylpiperidine)-propanone;    -   1-(1H-benzoimidazol-2-yl)-3-(4-ethylpiperidine)-propanone;    -   1-(1H-benzoimidazol-2-yl)-3-(4-n-propylpiperidine)-propanone;    -   1-(1H-benzoimidazol-2-yl)-3-(4-n-butylpiperidine)-propanone;    -   3-[3-(4-methylpiperidine)-1-yl-propyl]-1H-indazole;    -   3-[3-(4-ethylpiperidine)-1-yl-propyl]-1H-indazole;    -   3-[3-(4-n-propylpiperidine)-1-yl-propyl]-1H-indazole;    -   3-[3-(4-n-butylpiperidine)-1-yl-propyl]-1H-indazole;    -   1-(3-benzofuran-3-yl-propyl)-4-methyl-piperidine;    -   1-(3-benzofuran-3-yl-propyl)-4-ethyl-piperidine;    -   1-(3-benzofuran-3-yl-propyl)-4-n-propyl-piperidine;    -   1-(3-benzofuran-3-yl-propyl)-4-n-butyl-piperidine;    -   3-(3-(4-methylpiperidine)-1-yl-propyl)-benzo[d]isothiazole;    -   3-(3-(4-ethylpiperidine)-1-yl-propyl)-benzo[d]isothiazole;    -   3-(3-(4-n-propylpiperidine)-1-yl-propyl)-benzo[d]isothiazole;    -   3-(3-(4-n-butylpiperidine)-1-yl-propyl)-benzo[d]isothiazole;    -   1-[3-(4-methylpiperidine)-1-yl-propyl]-1H-benzoimidazole;    -   1-[3-(4-ethylpiperidine)-1-yl-propyl]-1H-benzoimidazole;    -   1-[3-(4-n-propylpiperidine)-1-yl-propyl]-1H-benzoimidazole;    -   1-[3-(4-n-butylpiperidine)-1-yl-propyl]-1H-benzoimidazole;    -   1-[2-(4-methylpiperidine)-1-yl-ethyl]-1H-benzoimidazole;    -   1-[2-(4-ethylpiperidine)-1-yl-ethyl]-1H-benzoimidazole;    -   1-[2-(4-n-propylpiperidine)-1-yl-ethyl]-1H-benzoimidazole;    -   1-[2-(4-n-butylpiperidine)-1-yl-ethyl]-1H-benzoimidazole;    -   1-[3-(4-methylpiperidine)-1-yl-propyl]-1H-indazole;    -   1-[3-(4-ethylpiperidine)-1-yl-propyl]-1H-indazole;    -   1-[3-(4-n-propylpiperidine)-1-yl-propyl]-1H-indazole;    -   1-[3-(4-n-butylpiperidine)-1-yl-propyl]-1H-indazole;    -   2-[4-(4-methylpiperidine)-1-yl-butyl]-1H-benzothiazole;    -   2-[4-(4-ethylpiperidine)-1-yl-butyl]-1H-benzothiazole;    -   2-[4-(4-n-propylpiperidine)-1-yl-butyl]-1H-benzothiazole;    -   2-[4-(4-n-butylpiperidine)-1-yl-butyl]-1H-benzothiazole;    -   2-[3-(4-methylpiperidine)-1-yl-propyl]-1H-benzothiazole;    -   2-[3-(4-ethylpiperidine)-1-yl-propyl]-1H-benzothiazole;    -   2-[3-(4-n-propylpiperidine)-1-yl-propyl]-1H-benzothiazole;    -   2-[3-(4-n-butylpiperidine)-1-yl-propyl]-1H-benzothiazole;    -   2-[2-(4-methylpiperidine)-1-yl-ethyl]-1H-benzothiazole;    -   2-[2-(4-ethylpiperidine)-1-yl-ethyl]-1H-benzothiazole;    -   2-[2-(4-n-propylpiperidine)-1-yl-ethyl]-1H-benzothiazole;    -   2-[2-(4-n-butylpiperidine)-1-yl-ethyl]-1H-benzothiazole;    -   2-[3-(4-methylpiperidine)-1-yl-propyl]-benzooxazole;    -   2-[3-(4-ethylpiperidine)-1-yl-propyl]-benzooxazole;    -   2-[3-(4-n-propylpiperidine)-1-yl-propyl]-benzooxazole;    -   2-[3-(4-n-butylpiperidine)-1-yl-propyl]-benzooxazole;    -   2-[2-(4-methylpiperidine)-1-yl-ethyl]-benzooxazole;    -   2-[2-(4-ethylpiperidine)-1-yl-ethyl]-benzooxazole;    -   2-[2-(4-n-propylpiperidine)-1-yl-ethyl]-benzooxazole;    -   2-[2-(4-n-butylpiperidine)-1-yl-ethyl]-benzooxazole;    -   2-[4-(4-methylpiperidine)-1-yl-butyl]-benzooxazole;    -   2-[4-(4-ethylpiperidine)-1-yl-butyl]-benzooxazole;    -   2-[4-(4-n-propylpiperidine)-1-yl-butyl]-benzooxazole;    -   2-[4-(4-n-butylpiperidine)-1-yl-butyl]-benzooxazole;    -   4,5-difluoro-2-(3-(4-n-butylpiperidine-1-yl)-propyl)-1H-benzoimidazole;    -   6-fluoro-5-nitro-2-(3-(4-n-butylpiperidine-1-yl)-propyl)-1H-benzoimidazole;    -   5-tert-butyl-2-(3-(4-n-butylpiperidine-1-yl)-propyl)-1H-benzoimidazole;    -   5-chloro-6-methyl-2-(3-(4-n-butylpiperidine-1-yl)-propyl)-1H-benzoimidazole;    -   4,6-difluoro-2-(3-(4-n-butylpiperidine-1-yl)-propyl)-1H-benzoimidazole;    -   2-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-imidazo[4,5-c]pyridine;    -   8-(3-(4-n-butylpiperidine)-1-yl-propyl)-9H-purine;    -   7-(3-(4-n-butylpiperidine)-1-yl-propyl)-3,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d][1,2,3]triazole;    -   2-(3-(4-n-butylpiperidine)-1-yl-propyl)-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;    -   3-methyl-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole;    -   5-bromo-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole;    -   3-formyl-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole;    -   7-bromo-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole;    -   3-(3-(4-n-butylpiperidine)-1-yl-propyl)-benzo[d]isoxazole;    -   4-nitro-2-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-benzoimidazole;    -   5-nitro-2-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-benzoimidazole    -   4-hydroxy-2-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-benzoimidazole;    -   4-methyl-2-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-benzoimidazole;    -   3-(2-(4-n-Butylpiperidine)-ethoxy)-7-methyl-benzo[d]isoxazole;    -   1-(3-(4-Methylpiperidine)-1-yl-propyl)-1H-indazole;    -   1-(3-(4-Pentylpiperidine)-1-yl-propyl)-1H-indazole;    -   1-(3-(4-Propylpiperidine)-1-yl-propyl)-1H—;    -   1-(3-(4-(3-Methyl-butyl)-piperidine)-1-yl-propyl)-1H-indazole    -   1-(3-(4-Pentylidene-piperidine)-1-yl-propyl)-1H-indazole;    -   1-(3-(4-Propylidene-piperidine)-1-yl-propyl)-1H-indazole        1-Benzo[b]thiophen-2-yl-4-(4-butylpiperidin-1-yl)-butan-1-one    -   4-(4-Butylpiperidin-1-yl)-1-(3-methyl-benzofuran-2-yl)-butan-1-one;    -   4-(4-Butylpiperidin-1-yl)-1-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-butan-1-one;    -   1-Benzofuran-2-yl-4-(4-butylpiperidin-1-yl)-butan-1-one;    -   1-(3-Bromo-benzo[b]thiophen-2-yl)-4-(4-butylpiperidin-1-yl)-butan-1-one    -   1-(3-Benzo[b]thiophen-2-yl-propyl)-4-butylpiperidine;    -   1-(3-Benzofuran-2-yl-propyl)-4-butylpiperidine;    -   4-Butyl-1-[3-(3-methyl-benzofuran-2-yl)-propyl]-piperidine;    -   4-Butyl-1-[3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-propyl]-piperidine;    -   2-(3-Iodo-propyl)-benzo[b]thiophene;    -   1-(3-Benzo[b]thiophen-2-yl-propyl)-4-methylpiperidine    -   1-(3-Benzo[b]thiophen-2-yl-propyl)-4-benzylpiperidine;    -   1-(3-Benzo[b]thiophen-2-yl-propyl)-4-(2-methoxy-phenyl)-piperidine;    -   2-(3-Bromopropyl)-2H-benzotriazole;    -   2-[3-(4-Butylpiperidin-1-yl)-propyl]-2H-benzotriazole;    -   1-(3-Bromopropyl)-1H-benzotriazole;    -   1-[3-(4-Butylpiperidin-1-yl)-propyl]-1H-benzotriazole;    -   1-[3-(4-Butylpiperidin-1-yl)-propyl]-1H-indole-3-carbaldehyde;    -   {1-[3-(4-Butylpiperidin-1-yl)-propyl]-1H-indol-3-yl}-methanol;    -   1-[3-(4-Butylpiperidin-1-yl)-propyl]-2-phenyl-1H-benzoimidazole;    -   1-[3-(4-Butylpiperidin-1-yl)-propyl]-3-chloro-1H-indazole;    -   1-[3-(4-Butylpiperidin-1-yl)-propyl]-6-nitro-1H-indazole;    -   Benzo[d]isoxazol-3-ol;    -   3-(2-Chloroethoxy)-benzo[d]isoxazole;    -   3-[2-(4-Butylpiperidin-1-yl)-ethoxy]-benzo[d]isoxazol;    -   3-(1H-Indol-3-yl)-propan-1-ol;    -   3-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indole hydrochloride;    -   4-(4-Butylpiperidine-1-yl)-butyric acid methyl ester;    -   2-[3-(4-Butylpiperidin-1-yl)-propyl]-1-methyl-1H-benzimidazole;    -   1H-Indazole-3-carboxylic acid        (2-(4-butylpiperidin)-1-yl-ethyl)-amide;    -   1-[3-(4-Butylpiperidin-1-yl)-propyl]-5-nitro-1H-indazole;    -   2-[3-(4-butylpiperidin-1-yl)-propyl]-5-nitro-2H-indazole;    -   1-[3-(4-Butyl-piperidin-1-yl)-propyl]-2-methyl-1H-indole;    -   1-{1-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indol-3-yl}-ethanone;    -   {1-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indol-3-yl}-acetonitrile;    -   1-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indole-3-carbonitrile;    -   1-[3-(4-Butyl-piperidin-1-yl)-propyl]-5,6-dimethyl-1H-benzoimidazole;    -   1-[3-(4-Butyl-piperidin-1-yl)-propyl]-5(6)-dimethyl-1H-benzoimidazole;    -   1-[3-(4-Butyl-piperidin-1-yl)-propyl]-5-methoxy-1H-benzoimidazole;    -   {1-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-benzoimidazol-2-yl}-methanol;    -   1-[3-(4-Butyl-piperidin-1-yl)-propyl]-2-trifuoromethyl-1H-benzoimidazole;    -   (2-Trimethylstannanyl-phenyl)-carbamic acid tert-butyl ester;    -   [2-(4-Chloro-butyryl)-phenyl]-carbamic acid tert-butyl ester;    -   {2-[4-(4-Butyl-piperidine-1-yl)-butyryl]-phenyl}-carbamic acid        tert-butyl ester;    -   3-[3-(4-Butyl-piperidine-1-yl)-propyl]-1H-indazole, HCl;    -   3-[3-(4-Butyl-piperidine-1-yl)-propyl]-5-nitro-1H-indazole;    -   3-[3-(4-Butyl-piperidine-1-yl)-propyl]-5,7-dinitro-1H-indazole;    -   4-(4-Butyl-piperidin-1-yl)-1-(2-metylsulfanyl-phenyl)-butan-1-one;    -   3-[3-(4-Butyl-piperidin-1-yl)-propyl]-benzo[d]isothiazole;    -   3-[3-(4-Butyl-piperidin-1-yl)-propyl]-5-methoxy-1H-indazole;    -   3-[3-(4-Butyl-piperidin-1-yl)-propyl]-4-methoxy-1H-indazole    -   3-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methoxy-1H-indazole;    -   3-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indazole-4-ol (53MF51);    -   3-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indazole-6-ol (53MF52);        and    -   3-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indazole-5-ol

The present invention further provides pharmaceutical compositionscomprising an effective amount of at least one compound of theinvention, inclusive of all compounds within the scope of formula (I).

In general, compounds of the present invention are active atcholinergic, specifically muscarinic receptors. Preferred compoundsshare the common property of acting as agonists at the m1 or m4muscarinic receptor subtypes, or both. In a preferred embodiment, thecompounds of the present invention are selective towards the m1, m4, orboth the m1 and m4 subtypes of muscarinic receptors, i.e., the compoundshave less or substantially no effect on other subtypes of the muscarinicreceptors. Typically, the m1 and/or m4 selective compounds of theinvention have no effect on other related receptors, including G-proteincoupled receptors, e.g., serotonin, histamine, dopamine or adrenergicreceptors. The invention provides compounds that are selective asagonists at either the m1 or the m4 subtype as well as compounds thatare agonists at both the m1 and m4 receptor subtypes. In one embodiment,the compounds of the present invention have less or substantially noeffect on m2 and m3 subtypes of muscarinic receptors. In anotherembodiment, the compounds of the present invention have less orsubstantially no effect on m2, m3, m4, and m5 subtypes of muscarinicreceptors.

The compounds of present invention typically have therapeutic effectsand can be used to treat or alleviate symptoms of disease conditionsassociated with cholinergic receptors such as cognitive impairment,forgetfulness, confusion, memory loss, attentional deficits, deficits invisual perception, depression, pain, sleep disorders, psychosis,hallucinations, aggressiveness, paranoia, and increased intraocularpressure. The disease condition may result from dysfunction, decreasedactivity, modification, mutation, truncation, or loss of cholinergicreceptors, especially muscarinic receptors, as well as from reducedlevels of acetylcholine.

The compounds of present invention can also be used to treat diseases,e.g., age-related cognitive decline, Alzheimer's disease, Parkinson'sdisease, Huntington's chorea, Friederich's ataxia, Gilles de laTourette's Syndrome, Down Syndrome, Pick disease, dementia, clinicaldepression, age-related cognitive decline, attention-deficit disorder,sudden infant death syndrome, and glaucoma.

The compounds of the present invention have the ability to increasecholinergic receptor activity or activate cholinergic receptors.Cholinergic receptor activity includes signaling activity or any otheractivity that is directly or indirectly related to cholinergic signalingor activation. The cholinergic receptors include muscarinic receptors,especially the m1 or m4 subtype of muscarinic receptors. The muscarinicreceptor can be, for example, in the central nervous system, peripheralnervous system, gastrointestinal system, heart, endocrine glands, orlungs. The muscarinic receptor can be a wild-type, truncated, mutated,or modified cholinergic receptor. Kits comprising the compounds of thepresent invention for increasing cholinergic receptor activity oractivating cholinergic receptors are also contemplated by the presentinvention.

The system containing the cholinergic receptor may, for example, be asubject such as a mammal, non-human primate or a human. The system mayalso be an in vivo or in vitro experimental model, such as a cellculture model system that expresses a cholinergic receptor, a cell-freeextract thereof that contains a cholinergic receptor, or a purifiedreceptor. Non-limiting examples of such systems are tissue culture cellsexpressing the receptor, or extracts or lysates thereof. Cells that maybe used in the present method include any cells capable of mediatingsignal transduction via cholinergic receptors, especially the m1muscarinic receptor, either via endogenous expression of this receptor(certain types of neuronal cells lines, for example, natively expressthe m1 receptor), or such as following introduction of the an exogenousgene into the cell, for example, by transfection of cells with plasmidscontaining the receptor gene. Such cells are typically mammalian cells(or other eukaryotic cells, such as insect cells or Xenopus oocytes),because cells of lower life forms generally lack the appropriate signaltransduction pathways for the present purpose. Examples of suitablecells include: the mouse fibroblast cell line NIH 3T3 (ATCC CRL 1658),which responds to transfected m1 receptors by increased growth; RAT 1cells (Pace et al., Proc. Natl. Acad. Sci. USA 88:7031–35 (1991)); andpituitary cells (Vallar et al., Nature 330:556–58 (1987)). Other usefulmammalian cells for the present method include but are not limited toHEK 293 cells, CHO cells and COS cells.

The compounds of the present invention also have the ability to reduceintraocular pressure and therefore can be used in the treatment of suchdiseases as glaucoma. Glaucoma is a disease in which an abnormality isobserved in the circulation-control mechanism of the aqueous humorfilling up the anterior chamber, i.e., the space formed between thecornea and the lens. This leads to an increase in the volume of theaqueous humor and an increase in intraocular pressure, consequentlyleading to visual field defects and even to loss of eyesight due to thecompulsion and contraction of the papillae of the optic nerve.

The present invention also pertains to the field of predictive medicinein which pharmacogenomics is used for prognostic (predictive) purposes.Pharmacogenomics deals with clinically significant hereditary variationsin the response to drugs due to altered drug disposition and abnormalaction in affected persons (see e.g., Eichelbaum, Clin Exp Pharmacol.Physiol., 23:983–985 (1996) and Linder, Clin. Chem. 43:254–66 (1997)).In general, two types of pharmacogenetic conditions can bedifferentiated: genetic conditions transmitted as a single factoraltering the way drugs act on the body (altered drug action) or geneticconditions transmitted as single factors altering the way the body actson drugs (altered drug metabolism). These pharmacogenetic conditions canoccur as naturally-occurring polymorphisms.

One pharmacogenomics approach to identifying genes that predict drugresponse, known as “a genome-wide association”, relies primarily on ahigh-resolution map of the human genome consisting of known gene-relatedmarkers (e.g., a “bi-allelic” gene marker map that consists of60,000–100,000 polymorphic or variable sites on the human genome, eachof which has two variants). Such a high-resolution genetic map can becompared to a map of the genome of each of a statistically significantnumber of patients taking part in a Phase II/III drug trial to identifymarkers associated with a particular observed drug response or sideeffect. Alternatively, such a high resolution map can be generated froma combination of some ten-million known single nucleotide polymorphisms(SNPs) in the human genome. As used herein, a “SNP” is a commonalteration that occurs in a single nucleotide base in a stretch of DNA.For example, a SNP may occur once per every 1,000 bases of DNA. A SNPmay be involved in a disease process although the vast majority may notbe disease-associated. Given a genetic map based on the occurrence ofsuch SNPs, individuals can be grouped into genetic categories dependingon a particular pattern of SNPs in their individual genome. In such amanner, treatment regimens can be tailored to groups of geneticallysimilar individuals, taking into account traits that may be common amongsuch genetically similar individuals.

Alternatively, a method termed the “candidate gene approach” can beutilized to identify genes that predict drug response. According to thismethod, if a gene that encodes a drug's target is known (e.g., a proteinor a receptor of the present invention), all common variants of thatgene can be identified in the population. It can be readily determinedby standard techniques a particular version of the gene is associatedwith a particular drug response.

Alternatively, a method termed “gene expression profiling” can beutilized to identify genes that predict drug response. For example, thegene expression of an animal dosed with a drug (e.g., a compound orcomposition of the present invention) can give an indication whethergene pathways related to toxicity have been turned on.

Information generated from more than one of the above pharmacogenomicsapproaches can be used to determine appropriate dosage and treatmentregimens for prophylactic or therapeutic treatment of an individual.This knowledge, when applied to dosing or drug selection, can avoidadverse reactions or therapeutic failure and thus enhance therapeutic orprophylactic efficiency when treating a subject with a compound orcomposition of the invention, such as a modulator identified by one ofthe exemplary screening assays described herein. These approaches canalso be used to identify novel candidate receptor or other genessuitable for further pharmacological characterization in vitro and invivo.

Accordingly, another aspect of the present invention features methodsand kits for identifying a genetic polymorphism predisposing a subjectto being responsive to a compound described herein. The method comprisesadministering to a subject an effective amount of a compound;identifying a responsive subject having an ameliorated disease conditionassociated with a cholinergic receptor; and identifying a geneticpolymorphism in the responsive subject, wherein the genetic polymorphismpredisposes a subject to being responsive to the compound. Identifying agenetic polymorphism in the responsive subject can be performed by anymeans known in the art including the methods discussed above. Inaddition, a kit to be used for identifying a genetic polymorphismpredisposing a subject to being responsive to a compound provided in thepresent invention comprises the compound of the present invention, andpreferably reagents and instructions for performing a geneticpolymorphism test.

In one embodiment, a subject can be tested for a known polymorphism thatpredisposes the subject to being responsive to the compound of thepresent invention. The presence of the polymorphism indicates that thesubject is suitable for treatment.

In preferred embodiments, the compounds of the present invention can berepresented as shown in formulae (IIIa–e):

-   -   where W₁ is O, S, or NR₅, W₂ is CR₅ or N, and W₃ is CR₅ or N, or    -   wherein W₃ is NR₅, S or O,    -   or a pharmaceutically acceptable salt, ester or prodrug thereof.

Compounds of the present invention may be prepared by methods analogousto the methods disclosed in G.B. Patent No. 1,142,143 and U.S. Pat. No.3,816,433, each of which are incorporated herein by reference. Ways ofmodifying those methods to include other reagents etc. will be apparentto those skilled in the art. Thus, for instance, compounds of formula(III, e.g., IIIb where W₁ is NR₅) may be prepared as shown in thefollowing reaction scheme.

The starting compound having formula (X) may be prepared by generalmethods of organic synthesis. For general methods of preparing compoundsof formula (X), reference is made to Fuller, et al., J. Med. Chem.14:322–325 (1971); Foye, et al., J. Pharm. Sci. 68:591–595 (1979);Bossier, et al., Chem. Abstr. 66:46195h and 67:21527a (1967); Aldous, J.Med. Chem. 17:1100–1111 (1974); Fuller, et al., J. Pharm. Pharmacol.25:828–829 (1973); Fuller, et al., Neuropharmacology 14:739–746 (1975);Conde, et al., J. Med. Chem. 21:978–981 (1978); Lukovits, et al., Int.J. Quantum Chem. 20:429–438 (1981); and Law, Cromatog. 407:1–18 (1987),the disclosures of which are incorporated by reference herein in theirentirety. Compounds of formula XI are prepared, for example, asdescribed in Darbre, et al., Helv. Chim. Acta, 67:1040–1052 (1984) orIhara, et al., Heterocycles, 20:421–424 (1983), also incorporated hereinby reference. The radiolabelled derivatives having formula (XX) may beprepared by, for example, using a tritiated reducing agent to form thereductive amination or by utilizing a ¹⁴C-labelled starting material.

Compounds of formula (XXII) can be used to prepare the compounds offormula (I). Compounds of formula (XXII) are prepared, for example, asdescribed in Ishii, et al., J. Org. Chem. 61:3088–3092 (1996) orBritton, et al. Bioorg. Med. Chem. Lett. 9:475–480 (1999), alsoincorporated herein by reference. Where the starting compound includes acarbonyl group, the compound having the formula (XXII) may be reducedwith, for example, AlH₃, diborane:methyl sulfide or other standardcarbonyl reducing reagents to produce the ligand having the formula(XXX).

The receptor ligands having formula (XXXII) may be prepared bynucleophilic displacement of a suitable nucleophuge (E) by the aminoderivative (XXXI). Examples of nucleophuges, which may be used for thispurpose, include halides such as I, Cl, Br, or tosylate or mesylate.

When Y in formula (XXX) is —C(O)—, this compound may be prepared fromoxidation of a secondary alcohol with, for example, pyridiniumchlorochromate, N-chlorosuccinimide, CrO₃—H₂SO₄, or via the Swern orDess-Martin procedures—nickel.

When Y in formula (XXX) is —O—, this compound may be prepared byarylation of an alcohol with arylhalides under, for example, Cucatalysis.

When Y in formula (XXX) is —S—, this compound may be prepared byarylation of a thiol with arylhalides under, for example, Cu catalysis.

When Y in formula (XXX) is —CHOH—, this compound may be prepared byreduction of the corresponding ketone by catalytic hydrogenation or bythe use of NaBH₄ or by the use of LiAlH₄.

Suitable pharmaceutically acceptable salts of the compounds of thisinvention include acid addition salts which may, for example, be formedby mixing a solution of the compound according to the invention with asolution of a pharmaceutically acceptable acid such as hydrochloricacid, sulphuric acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Examples of pharmaceutically acceptable salts include theacetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium, carbonate, chloride, clavulanate, citrate,dihydrochloride, fumarate, gluconate, glutamate, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, maleate, mandelate, mesylate, methylbromide,methylnitrate, methylsulfate, nitrate, N-methylglucamine ammonium sal,oleate, oxalate, phosphate/diphosphate, salicylate, stearate, sulfate,succinate, tannate, tartrate, tosylate, triethiodide and valerate salt.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs are derivativesof the compounds of this invention, which are readily convertible invivo into the required compound. Conventional procedures for theselection and preparation of suitable prodrug derivatives are described,for example, in Design of Prodrugs, (Bundgaard, ed. Elsevier, 1985).Metabolites of these compounds include active species produced uponintroduction of compounds of this invention into the biological milieu.

Where the compounds according to the invention have at least one chiralcenter, they may exist as a racemate or as enantiomers. It should benoted that all such isomers and mixtures thereof are included in thescope of the present invention. Furthermore, some of the crystallineforms for compounds of the present invention may exist as polymorphs andas such are intended to be included in the present invention. Inaddition, some of the compounds of the present invention may formsolvates with water (i.e., hydrates) or common organic solvents. Suchsolvates are also included in the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixtures of stereoisomers, such isomers maybe separated by conventional techniques such as preparative chiralchromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by stereoselectivesynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry (McOmie ed., PlenumPress, 1973); and Greene & Wuts, Protective Groups in Organic Synthesis(John Wiley & Sons, 1991) The protecting groups may be removed at aconvenient subsequent stage using methods known from the art.

Compounds of the present invention may be administered in any of theforegoing compositions and according to dosage regimens established inthe art whenever specific pharmacological modification of the activityof muscarinic receptors is required.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of the invention together with apharmaceutically acceptable diluent or excipient. Preferably suchcompositions are in unit dosage forms such as tablets, pills, capsules(including sustained-release or delayed-release formulations), powders,granules, elixirs, tinctures, syrups and emulsions, sterile parenteralsolutions or suspensions, aerosol or liquid sprays, drops, ampoules,auto-injector devices or suppositories; for oral, parenteral (e.g.,intravenous, intramuscular or subcutaneous), intranasal, sublingual orrectal administration, or for administration by inhalation orinsufflation, and may be formulated in an appropriate manner and inaccordance with accepted practices such as those disclosed in Remington's Pharmaceutical Sciences (Gennaro, ed., Mack Publishing Co., EastonPa., 1990). Alternatively, the compositions may be in sustained-releaseform suitable for once-weekly or once-monthly administration; forexample, an insoluble salt of the active compound, such as the decanoatesalt, may be adapted to provide a depot preparation for intramuscularinjection. The present invention also contemplates providing suitabletopical formulations for administration to, e.g., eye, skin or mucosa.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents, flavoring agentsand coloring agents can also be incorporated into the mixture. Suitablebinders include, without limitation, starch, gelatin, natural sugarssuch as glucose or beta-lactose, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include, without limitation, sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

For preparing solid compositions such as tablets, the active ingredientis mixed with a suitable pharmaceutical excipient, e.g., such as theones described above, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the present invention, or a pharmaceutically acceptablesalt thereof. By the term “homogeneous” is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. The solid preformulationcomposition may then be subdivided into unit dosage forms of the typedescribed above containing from about 0.01 to about 50 mg of the activeingredient of the present invention. The tablets or pills of the presentcomposition may be coated or otherwise compounded to provide a dosageform affording the advantage of prolonged action. For example, thetablet or pill can comprise an inner core containing the active compoundand an outer layer as a coating surrounding the core. The outer coatingmay be an enteric layer, which serves to resist disintegration in thestomach and permits the inner core to pass intact into the duodenum orto be delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric acids and mixtures of polymeric acids with conventionalmaterials such as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the present compositions may be incorporatedfor administration orally or by injection include aqueous solutions,suitably flavored syrups, aqueous or oil suspensions, and flavoredemulsions with edible oils such as cottonseed oil, sesame oil, coconutoil or peanut oil, as well as elixirs and similar pharmaceuticalcarriers. Suitable dispersing or suspending agents for aqueoussuspensions include synthetic and natural gums such as tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose, gelatin,methylcellulose or polyvinyl-pyrrolidone. Other dispersing agents, whichmay be employed, include glycerin and the like. For parenteraladministration, sterile suspensions and solutions are desired. Isotonicpreparations, which generally contain suitable preservatives, areemployed when intravenous administration is desired. The compositionscan also be formulated as an ophthalmic solution or suspensionformation, i.e., eye drops, for ocular administration

Compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided dosestwo, three or four times daily. Furthermore, compounds of the presentinvention may be administered in intranasal form via topical use ofsuitable intranasal vehicles or via transdermal routes, using e.g.,forms of transdermal skin patches that are well known to persons skilledin the art. To be administered in the form of a transdermal deliverysystem, the dosage administration will be continuous rather thanintermittent throughout the dosage regimen.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound employed. A physician or veterinarian of ordinary skill canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the disease ordisorder, which is being treated.

The daily dosage of the products may be varied over a wide range from0.01 to 100 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0 or 50.0 mg of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. A unit dose typically contains from about 0.001mg to about 50 mg of the active ingredient, preferably from about 1 mgto about 10 mg of active ingredient. An effective amount of the drug isordinarily supplied at a dosage level of from about 0.0001 mg/kg toabout 25 mg/kg of body weight per day. Preferably, the range is fromabout 0.001 to 10 mg/kg of body weight per day, and especially fromabout 0.001 mg/kg to 1 mg/kg of body weight per day. The compounds maybe administered, for example, on a regimen of 1 to 4 times per day.

Compounds according to the present invention may be used alone atappropriate dosages defined by routine testing in order to obtainoptimal pharmacological effect on a muscarinic receptor, in particularthe muscarinic m1 or m4 receptor subtype, while minimizing any potentialtoxic or otherwise unwanted effects. In addition, co-administration orsequential administration of other agents that improve the effect of thecompound may, in some cases, be desirable.

The pharmacological properties and the selectivity of the compounds ofthis invention for specific muscarinic receptor subtypes may bedemonstrated by a number of different assay methods using, for example,recombinant receptor subtypes, preferably of the human receptors asavailable, e.g., conventional second messenger or binding assays. Aparticularly convenient functional assay system is the receptorselection and amplification assay disclosed in U.S. Pat. No. 5,707,798,which describes a method of screening for bioactive compounds byutilizing the ability of cells transfected with receptor DNA, e.g.,coding for the different muscarinic subtypes, to amplify in the presenceof a ligand of the receptor. Cell amplification is detected as increasedlevels of a marker also expressed by the cells.

The invention is disclosed in further detail in the following examples,which are not in any way intended to limit the scope of the invention asclaimed.

EXAMPLES

Methods of Preparation

The compounds in accordance with the present invention may besynthesized by methods described below, or by modification of thesemethods. Ways of modifying the methodology include, for example,temperature, solvent, reagents etc, will be apparent to those skilled inthe art.

General LC-MS procedure: All spectra were obtained using an HP1100LC/MSD-instrument. A setup with a binary pump, autosampler, column oven,diode array detecter, and electrospray ionization interface was used. Areversed-phase column (C18 Luna 3 mm particle size, 7.5 cm×4.6 mm ID)with a guard cartridge system was used. The column was maintained at atemperature of 30° C. The mobile phase was acetonitrile/8 mM aqueousammonium acetate. A 15 minute gradient program was used, starting at 70%acetonitrile over 12 minutes to 95% acetonitrile over 1 minute back to70% acetonitrile, where it stayed for 2 minutes. The flow rate was 0.6ml/min. The t_(r) values reported in the specific examples below wereobtained using this procedure.

2-(3-(4-n-Butylpiperidine-1-yl)-propyl)-benzothiazole (5).1-Benzyl-4-n-butylidenepiperidine (2). A 500 mL 3-necked flask fittedwith a stirrer was charged with sodium hydride (1.61 g, 67 mmol) andDMSO (40 mL). The resulting suspension was heated to 90° C. for 30minutes, until the evolution of hydrogen ceased. The suspension wascooled on an ice-bath for 20 minutes followed by addition of a slurry ofbutyltriphenylphosphonium bromide (26.6 g, 67 mmol) in DMSO (70 mL). Thered mixture was stirred for 15 min at room temperature.1-Benzyl-4-piperidone 1 (14.0 g, 74 mmol) was slowly added over 30 min,and the mixture was stirred at room temperature over night. H₂O (200 mL)was added to the reaction mixture followed by extraction with heptane(4×100 mL) and ethyl acetate (2×100 mL). The combined organic phaseswere dried and evaporated to dryness, producing 38.1 g of a yellow oil.The oil was distilled to give 14.9 g (88%) of 2, bp 101–105° C. (0.1 mmHg). ¹H NMR (CDCl₃) δ 0.90–0.95 (t, 3H), 1.25–1.41 (m, 2H), 1.90–2.20(m, 2H), 2.1–2.30 (m, 4H), 2.40–2.45 (m, 4H), 2.50 (s, 2H), 5.17 (t,1H), 7.20–7.42 (m, 5H).

4-n-Butylpiperidine (3). In a 500 mL flask fitted with a stirrer wasadded a slurry of 2 (13.2 g, 58 mmol) and 10% palladium on charcoal (1.2g) in ethanol (70 mL), followed by addition of concentrated hydrochloricacid (1.5 mL). The reaction flask was evacuated and hydrogen was addedvia a reaction flask. A total of 2.5 dm³ of hydrogen was consumed. Thereaction mixture was filtered and evaporated and the residue wasdissolved in H₂O (40 mL) and NaOH (20 mL, 2 M) followed by extractionwith ethyl acetate (3×100 mL). The combined organic phases were washedwith brine (30 mL) and evaporated to dryness to produce 7.1 g of crude3. The crude product was subjected to column chromatography(eluent:heptane:EtOAc (4:1)) to give pure 3 (2.7 g, 33%). ¹H NMR (CDCl₃)δ 0.85 (t, 3H), 1.0–1.38 (m, 9H), 1.65 (dd, 2H), 2.38 (s, 1H), 2.55 (dt,2H), 3.04 (dt, 2H).

4-(4-n-Butylpiperidin-1-yl)butyric acid methyl ester (4). A 50 mL flaskwas charged with a mixture of 3 (2.7 g, 15 mmol), 4-bromo butyric acidmethyl ester (9.9 g, 55 mmol) and potassium carbonate (8.6 g, 62 mmol)in acetonitrile (25 mL). The mixture was stirred at room temperature for72 hours followed by evaporation to dryness. The crude product wassubjected to column chromatography (eluent:CH₂Cl₂:CH₃OH (96:4)) toproduce pure 4 (3.4 g, 94%). ¹H NMR (CDCl₃) δ 0.89 (t, 3H), 1.20–1.39(m, 9H), 1.69 (d, 2H), 1.89 (qv, 2H), 1.98 (t, 2H), 2.36 (t, 2H), 2.43(t, 2H), 3.99 (d, 2H), 3.67 (s, 3H).

General Procedure for the Preparation of2-(3-(4-n-butylpiperidine-1-yl)-propyl) heteroaromatics (5, 6, 7, 8, 9,10, 11, 12, 13).

A small sealed vial equipped with a magnetic stirrer, charged with 4(121 mg, 0.50 mmol), the appropriate benzdiamines (listed under eachcompound) (0.55 mmol) and polyphosphoric acid (2.1 g) was heated to 150°C. for 2 hours. The reaction mixture was poured into ice water andneutralized with sodium bicarbonate and filtered. Further treatment ofthe filtrate with 2 M NaOH produced additional crystals, which werefiltered and combined with the earlier crop followed by washing, dried,and recrystallized from ether.

Example 1 2-(3-(4-n-Butylpiperidine-1-yl)-propyl)benzothiazole (5)(34JJ15)

2-Amino-benzenethiol was used as starting material and the generalprocedure was followed to produce pure 5 (70 mg, 43%). ¹H NMR (CDCl₃) δ0.88 (t, 3H), 1.08–1.20 (m, 2H), 1.50 (m, 2H), 1.55–1.70 (m, 7H), 1.72(qv, 2H), 1.73–1.75 (m, 2H), 2.35–2,39 (m, 2H), 2.41 (t, 2H), 2.61 (t,2H), 7.39(dt, 2H), 7.89(dd, 2H).

Example 2 2-(3-(4-n-Butylpiperidine-1-yl)-propyl)-benzooxazole (6)(34JJ17)

2-Amino-phenol was used as starting material and the general procedurewas followed to produce pure 6 (137 mg, 83%). ¹H NMR (CDCl₃) δ 0.88 (t,3H), 1.18–1.32 (m, 10H), 1.65 (d, 2H), 1.95 (t, 2H), 2.12 (qv, 2H), 2.49(t, 2H), 2.92–3.00 (m, 3H), 7.28–7.32 (m, 2H), 7.45–7.50 (m, 1H),7.64–7.68 (m, 1H).

Example 34,5-Difluoro-2-(3-(4-n-butylpiperidine-1-yl)-propyl)-1H-benzoimidazole(7) (34JJ21)

3,4-Difluoro-1,2-diaminobenzene was used as starting material and thegeneral procedure was followed to produce pure 7 (55 mg, 30%). ¹H NMR(CDCl₃) δ 0.93 (t, 3H), 1.30–1.44 (m, 9H), 1.82 (d, 2H), 1.98 (qv, 2H),2.09 (t, 2H), 2.63 (dt, 2H), 3.07 (d, 2H), 3.14 (dt, 2H), 6.95–7.03 (m,1H), 7.16–7.21 (m, 1H).

Example 46-Fluoro-5-nitro-2-(3-(4-n-butylpiperidine-1-yl)-propyl)-1N-benzoimidazole(8) (34JJ13)

4-Fluoro-5-nitro-1,2-diaminobenzene was used as starting material andthe general procedure was followed to produce pure 8 (12 mg, 6%). ¹H NMR(CDCl₃) δ 0.93 (t, 3H), 1.30–1.54 (m, 7H), 1.60 (q, 2H), 1.93 (d, 2H),2.22 (qv, 2H), 2.42 (t, 2H), 2.82 (t, 2H), 3.24 (t, 2H), 3.31 (d, 2H),7.34 (d, 1H), 8.29 (d, 1H).

Example 55-tert-Butyl-2-(3-(4-n-butylpiperidine-1-yl)-propyl)-1H-benzoimidazole(9) (23JJ83)

4-tert-Butyl-1,2-diaminobenzene was used as starting material and thegeneral procedure was followed to produce pure 9 (74 mg, 38%). ¹H NMR(CDCl₃) δ 0.93 (t, 3H), 1.30–1.42 (m, 18H), 1.81 (d, 2H), 1.96 (qv, 2H),2.04 (t, 2H), 2.55 (t, 2H), 3.02 (d, 2H), 3.07 (t, 2H), 7.26 (dd, 1H),7.45 (d, 1H), 7.53 (d, 1H).

Example 65-Chloro-6-methyl-2-(3-(4-n-butylpiperidine-1-yl)-propyl)-1H-benzoimidazole(10) (23JJ93)

4-Chloro-5-methyl-1,2-diaminobenzene was used as starting material andthe general procedure was followed to produce pure 10 (7 mg, 3%). ¹H NMR(CDCl₃) δ 0.94 (t, 3H), 1.30–1.41 (m, 9H), 1.83 (d, 2H), 1.95 (qv, 2H),2.08 (t, 2H), 2.46 (s, 3H), 2.57 (t, 2H), 3.04 (d, 2H), 3.09 (t, 2H),7.32 (s, 1H), 7.50 (s, 1H).

Example 74,6-Difluoro-2-(3-(4-n-butylpiperidine-1-yl)-propyl)-1H-benzoimidazole(11) (23JJ77)

3,5-Difluoro-1,2-diaminobenzene was used as starting material and thegeneral procedure was followed to produce pure 11 (50 mg, 27%). ¹H NMR(CDCl₃) δ 0.92 (t, 3H), 1.22–1.43 (m, 7H), 1.56 (q, 2H), 1.87 (d, 2H),2.13 (qv, 2H), 2.38 (t, 2H), 2.87 (t, 2H), 3.19 (t, 2H), 2.29 (d, 2H),6.69 (dt, 1H), 7.02 (dd, 1H).

Example 82-(3-(4-n-Butylpiperidine)-1-yl-propyl)-1H-imidazo[4,5-c]pyridine (12)(23JJ81)

Pyridine-3,4-diamine was used as starting material and the generalprocedure was followed to produce pure 12 (18 mg, 11%). ¹H NMR (CDCl₃) δ0.94 (t, 3H), 1.30–1.42 (m, 9H), 1.87 (d, 2H), 2.01 (qv, 2H), 2.13 (t,2H), 2.64 (t, 2H), 3.08 (d, 2H), 3.17 (t, 2H), 7.41 (d, 1H), 8.35 (d,1H), 8.90 (s, 1H).

Example 9 8-(3-(4-n-Butylpiperidine)-1-yl-propyl)-9H-purine (13)(34JJ27)

Pyrimidine-4,5-diamine was used as starting material and the generalprocedure was followed to produce pure 12 (94 mg, 57%). ¹H NMR (MeOD) δ0.92 (t, 3H), 1.29–1.39 (m, 6H), 1.43–1.60 (m, 3H), 2.00 (d, 2H), 2.43(qv, 2H), 3.00 (t, 2H), 3.21–3.35 (m, 4H), 3.64 (d, 2H), 9.25 (s, 1H),9.38 (s, 1H).

Example 107-(3-(4-n-Butylpiperidine)-1-yl-propyl)-3,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d][1,2,3]triazole(14) (34JJ39)

1H-Benzotriazole-4,5-diamine was used as starting material and thegeneral procedure was followed to produce pure 14 (24 mg, 13%). ¹H NMR(DMSO) δ 0.83 (t, 3H), 1.00–1.28 (m, 9H), 1.57 (d, 2H), 1.80 (t, 2H),1.94 (qv, 2H), 2.32 (t, 2H), 2.82 (d, 2H), 2.88 (t, 2H), 7.49 (d, 1H),7.62 (d, 1H).

Example 112-(3-(4-n-Butylpiperidine)-1-yl-propyl)-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole(15)

Cyclohexane-1,2-diamine was used as starting material and the generalprocedure was followed to produce pure 15 (79 mg, 47%). 1H NMR (CDCl3) δ0.80–1.05 (m, 11H), 1.27–1.75 (m, 17H), 2.57 (t, 2H), 2.66 (t, 2H), 3.57(q, 1H), 4.48 (q, 1H).

General Procedure for the Preparation of Substituted Indole Derivatives(16, 17, 18, 19, 20 and 21). 1,3-Dibromopropane (205 μl, 2.0 mmol) in 5mL DMF was placed in a 50 mL flask. The appropriate indole (2.0 mmol)and KOH (280 mg, 5.0 mmol) was partly dissolved in 5 mL DMF and addedduring stirring. Resulting suspension was stirred overnight at roomtemperature. 4-Butylpiperidine (3) (178 mg, 1.0 mmol) in 5 mL DMF wasadded and the mixture was stirred overnight at room temperature. Ethylacetate (20 mL) and water (20 mL) were added. The phases were separatedand the aqueous phase was re-extracted with ethyl acetate (20 mL). Thecombined organic phases were washed with brine, dried over magnesiumsulphate and evaporated to dryness to produce crude product. Crudeproduct was purified by column chromatography (0–5%methanol:dichloromethane) to produce pure products.

Example 12 1-(3-(4-n-Butylpiperidine)-1-yl-propyl)-1H-indole (16)(35AKU-15)

1H-Indole was used as starting material and the general procedure wasfollowed to produce pure 16 (69 mg, 23%). ¹H NMR (CDCl₃) δ 0.9 (t, 3H),1.2–1.3 (m, 7H), 1.5 (q, 2H), 1.75 (d, 2H), 2.1–2.3 (m, 4H), 2.5 (t,2H), 3.1 (d, 2H), 4.25 (t, 2H), 6.5 (d, 1H), 7.1 (m, 2H), 7.2 (t, 1H),7.35 (d, 1H), 7.6 (d, 1H).

Example 13 1-(3-(4-n-Butylpiperidine)-1-yl-propyl)-1H-benzoimidazole(17) (35AKU-16)

1H-Benzoimidazole was used as starting material and the generalprocedure was followed to produce pure 17 (69 mg, 23%). ¹H NMR (CDCl₃) δ0.9 (t, 3H), 1.2–1.3 (m, 7H), 1.5 (q, 2H), 1.75 (d, 2H), 2.25 (m, 4H),2.6 (t, 2H), 3.1 (d, 2H), 4.3 (t, 2H), 7.2–7.3 (m, 2H), 7.45 (d, 1H),7.75 (d, 1H), 8.0 (s, 1H).

Example 14 3-Methyl-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole(18) (35AKU-22)

3-Methyl-1H-indole was used as starting material and the generalprocedure was followed to produce pure 18. ¹H NMR (CDCl₃) δ 0.9 (t, 3H),1.2–1.3 (m, 9H), 1.65 (d, 2H), 1.9 (t, 2H), 2.0 (m, 2H), 2.25 (m, 2H),2.3 (s, 3H), 2.85 (d, 2H), 4.1 (t, 2H), 6.85 (s, 1H), 7.1 (t, 1H), 7.2(t, 1H), 7.55 (d, 1H).

Example 15 5-Bromo-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole(19) (35AKU-23)

5-Bromo-1H-indole was used as starting material and the generalprocedure was followed to produce pure 19. ¹H NMR (CDCl₃) δ 0.9 (t, 3H),1.2–1.3(m, 9H), 1.65 (d, 2H), 1.85 (t, 2H), 2.0 (t, 2H), 2.2 (t, 2H),2.8 (d, 2H), 4.15 (t, 2H), 6.4 (d, 1H), 7.1 (d, 1H), 7.25 (m, 2H), 7.75(s, 1H).

Example 16 3-Formyl-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole(20) (35AKU-24)

3-Formyl-1H-Indole was used as starting material and the generalprocedure was followed to produce pure 20. ¹H NMR (CDCl₃) δ 0.9 (t, 3H),1.2–1.3 (m, 9H), 1.7 (d, 2H), 1.95 (t, 2H), 2.1 (m, 2H), 2.3 (t, 2H),2.9 (d, 2H), 4.3 (t, 2H), 7.3–7.5 (m, 3H), 8.3 (m, 1H), 10.0 (s, 1H).

Example 17 7-Bromo-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole(21) 35AKU-25)

7-Bromo-1H-indole was used as starting material and the generalprocedure was followed to produce pure 21. ¹H NMR (CDCl₃) δ 0.9 (t, 3H),1.2–1.3 (m, 9H), 1.65 (d, 2H), 1.9 (t, 2H), 2.05 (m, 2H), 2.3 (t, 2H),2.9 (d, 2H), 4.55 (t, 2H), 6.45 (d, 1H), 6.9 (t, 1H), 7.1 (d, 1H), 7.35(d, 1H), 7.55 (d, 1H).

Example 18 1-(3-Bromo-propyl)-1H-indazole (22)

1,3-Dibromopropane (508 μl, 5.0 mmol)) was dissolved in 10 mL DMF andplaced in a 100 mL flask. Indazole (592 mg, 5.0 mmol) and KOH (282 mg,5.0 mmol) were added and the suspension was stirred overnight at roomtemperature. Ethyl acetate (50 mL) and water (50 mL) were added. Phaseswere separated and the aqueous phase was re-extracted with ethyl acetate(50 mL). The combined organic phases were washed with brine, dried overmagnesium sulphate and evaporated to dryness to produce 751 mg of ayellow oil. Crude product was further purified by column chromatography(0–10% methanol:dichloromethane) to produce pure 22 (169 mg, 14%).

Example 19 1-(3-(4-n-Butylpiperidine)-1-yl-propyl)-1H-indazole (23)(35AKU-21)

To a 50 mL flask was added 22 (169 mg, 0.7 mmol) and 10 mL DMF.4-Butylpiperidine (3) (142 mg, 1.0 mmol) and KOH (113 mg, 2.0 mmol) werepartly dissolved in DMF (5 mL) and added. The suspension was stirredovernight at room temperature. Ethyl acetate (20 mL) and water (20 mL)were added. The phases were separated and the aqueous phase wasre-extracted with ethyl acetate (20 mL). The combined organic phaseswere washed with brine, dried over magnesium sulphate and evaporated todryness to give 192 mg of light brown oil. Crude product was purified bycolumn chromatography (0–10% methanol:dichloromethane) to produce pureproduct 23 (61 mg, 29%). Oxalate-salt was prepared from oxalic acid (1.1eq.) in methanol/diethylether. ¹H NMR (CDCl₃) δ 0.9 (t, 3H), 1.2–1.3 (m,9H), 1.65 (d, 2H) 1.9 (t, 2H), 2.15 (m, 2H), 2.3 (t, 2H), 2.85 (d, 2H),4.45 (t, 2H), 7.1 (t, 1H), 7.35 (t, 1H), 7.5 (d, 1H), 7.7 (d, 1H), 8.0(s, 1H).

Example 20 1-(2-Hydroxy-phenyl)-ethanone oxime (24)

Hydroxylammoniumchloride (6.96 g, 100 mmol) and sodium acetate. 3H₂O(13.6 g, 100 mmol) were dissolved in 150 mL ethanol:water (7:3) andadded to a solution of 2-hydroxyacetophenone (6.81 g, 50 mmol) in 50 mLethanol:water (7:3). The pH was adjusted to 4–5 with 4N HCl (˜10 mL) andthe reaction mixture was then heated to reflux (100° C.) for 1 hour. Theoil bath was removed and the mixture was left overnight with stirring.Ethanol was partly removed by evaporation and the aqueous phase wasextracted with ethyl acetate two times. The combined organic phases weredried over magnesium sulphate and evaporated to dryness to produce 7.55g of pure 24.

Example 21 3-Methyl-benzo[d]isoxazole (25)

Acetic anhydride (7.1 mL, 75 mmol) was added to 24 (7.55 g, 50 mmol) ina 100 mL flask. The mixture was heated to 60° C. for 3 hours followed byevaporation to dryness. Potassium carbonate (8.7 g, 63 mmol) was partlydissolved in 40 mL DMF and added to the mixture. The mixture was stirredat room temperature overnight and finally heated to 100° C. for 30minutes. Ethyl acetate and water were added. The phases were separatedand the aqueous phase was extracted with ethyl acetate anddichloromethane. The combined organic phases were dried over magnesiumsulphate and evaporated to dryness to give 5.6 g of a yellow oil. Crudeproduct was purified by column chromatography (100% dichloromethane),producing pure 25 (4.6 g). ¹H NMR (CDCl₃) δ 2.6 (s, 3H), 7.3 (m, 1H),7.55 (m, 2H), 7.65 (m, 1H).

Example 22 3-But-3-enyl-benzo[d]isoxazole (26)

3.0 mL dry THF was added to an oven-dried 25 mL flask and cooled to −78°C. on a dry ice/isopropanol bath. Diisopropylamine (840 μl, 6.0 mmol)was added followed by n-BuLi (3.8 mL, 1.6 M, 6.0 mmol). The LDA-solutionthat was obtained was left at room temperature. Compound 25 (666 mg, 5.0mmol) was dissolved in 10 mL dry THF and added to an oven-dried 50 mLflask followed by allylbromide (476 μl, 5.5 mmol). The freshly preparedLDA-solution was slowly added at −78° C. and the mixture was left atroom temperature for 30 min. Ethyl acetate and water were added. Thephases were separated and the aqueous phase was extracted with ethylacetate. The combined organic phases were dried over magnesium sulphateand evaporated to dryness to produce 893 mg of a light brown oil. Crudeproduct was purified by column chromatography (heptane:ethyl acetate;9:1; isocratic) to produce pure 26 (355 mg, 41%).

Example 23 3-(Benzo[d]isoxazol-3-yl)-propionaldehyde (27)

Compound 26 (549 mg, 3.2 mmol), water (5 mL), 1,4-dioxane (15 mL) andosmium tetroxide (15 mg, 0.06 mmol) were stirred for 5 min. in a smallflask. Sodium metaperiodate (1.56 g, 7.3 mmol) was added over 30 min.and the suspension was then stirred for 1 hour. Ethyl acetate and waterwere added. The phases were separated and the aqueous phase wasextracted with ethyl acetate and dichloromethane. The combined organicphases were dried over magnesium sulphate and evaporated to dryness toproduce 784 mg of crude 27, which was used directly without furtherpurification in the synthesis compound 28.

Example 24 3-(3-(4-n-Butylpiperidine)-1-yl-propyl)-benzo[d]isoxazole(28) (35AKU-2)

Compound 27 (˜500 mg, 2–3 mmol) was dissolved in 5 mL methanol.4-Butylpiperidine. HCl 3 (260 mg, 1.5 mmol) was dissolved in 10 mLmethanol and added. Sodium cyanoborohydride (188 mg, 3.0 mmol) in 10 mLmethanol was added, giving a dark brown solution which was stirredovernight. Water was added and methanol was partly removed byevaporation. The aqueous phase was extracted with ethyl acetate anddichloromethane. The combined organic phases were dried over magnesiumsulphate and evaporated to dryness. The crude product was furtherpurified by preparative HPLC (mobile phase 0–80% acetonitrile in water(0.1% TFA)) giving 28 (244 mg, 54%). HCl-salt was prepared from 2M HClin diethylether. The crystals were filtered and washed by diethylether.¹H-NMR (CDCl₃) δ 0.9 (t, 3H), 1.2–1.3 (m, 9H), 1.65 (d, 2H), 1.9 (t,2H), 2.05 (m, 2H), 2.45 (t, 2H), 2.9 (d, 2H), 3.0 (t, 2H), 7.3 (m, 1H),7.55 (m, 2H), 7.7 (d, 1H).

Example 25 3-(1H-Indol-3-yl)-propan-1-ol (29)

A suspension of lithium aluminum hydride (4.68 g, 126 mmol) in 230 mLanhydrous diethylether was stirred heavily. 3-Indole propionic acid(10.0 g, 53 mmol) dissolved in 460 mL anhydrous diethylether wastransferred to a dropping funnel and added at such a rate that gentlereflux was maintained. The reaction mixture was left with stirring atreflux temperature for 2 h, then at room temperature overnight. Thenreflux was continued for 2 h before cooling to room temperature. 25 mLH₂O was slowly added followed by 70 mL H₂O/H₂SO₄ (1:3 H₂O/H₂SO₄). Theresulting clear mixture was extracted with 110 mL diethylether threetimes. The combined organic phases were washed with brine, dried withNa₂SO₄, filtrated and concentrated to bright oil, which was used withoutfurther purification.

Example 26 Methanesulfonic acid 3-(1H-indole-3-yl)-propyl ester (30)

Compound 29 (1.8 g, 5.44 mmol) was transferred to a flame-dried flaskfilled with argon and dissolved in anhydrous THF then cooled to −40° C.Triethylamine (0.72 g, 7.07 mmol) was added by syringe followed byMeSO₂Cl (0.75 g, 6.53 mmol). The temperature of the reaction mixture wasallowed to rise to room temperature (10–15 minutes) before it wasquickly filtrated and concentrated. The crude oil was dissolved inCH₂Cl₂ and washed with H₂O. The organic phase was dried with MgSO₄,filtrated and concentrated in vacuo to a dark, brown oil. The crudeproduct was used immediately in the next step.

Example 27 3-(3-(4-n-Butylpiperidine)-1-yl-propyl)-1H-indole (31)(39MF34)

Na₂CO₃ (1.28 g, 11.97 mmol) was added to a solution of 4-butylpiperidinehydrochloride 3 (967 mg, 5.44 mmol) in anhydrous DME. The resultingsuspension was stirred for 30 min. Compound 30 was dissolved inanhydrous DME and added to the suspension. The resulting mixture wasstirred under argon at 82° C. over night. The mixture was cooled, EtOAcand H₂O was added, the two phases were separated, and the water wasextracted with EtOAc three times. The combined organic phases werewashed with brine, dried with Na₂SO₄, filtrated and concentrated invacuo. The crude oil was dissolved in anhydrous CH₂Cl₂ and HCl indioxane (4M, 2 mL) was added. The product (31) was isolated as whitecrystals by recrystallization from MeOH/diethylether. ¹H-NMR (CDCl₃) δ0.93 (t, 3H), 1.32–1.58 (m, 7H), 1.60 (q, 2H), 1.93 (d, 2H), 2.22 (qv,2H), 2.42 (t, 2H), 2.82 (t, 2H), 3.24 (t, 2H), 3.31 (d, 2H), 6.91–7.10(m, 2H), 7.34 (d, 1H), 7.53 (d, 1H).

Example 284-Nitro-2-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-benzoimidazole (32)(29MF03)

A 25 mL flask fitted with a condenser and a magnetic stirrer was chargedwith 1,2-diamino-3-nitrobenzene (0.251 g, 1.64 mmol) and4-(4-n-butylpiperidin-1-yl)-butyric acid methyl ester (4) (0.395 g, 1.64mmol) in 5 mL 4 M HCl. The reaction was refluxed for 24 h followed byaddition of 2.0 M NaOH to produce basic conditions, stirred at roomtemperature for 1 h and extracted with ethyl acetate (5×50 mL). Thecombined organic phases were washed with 15 mL brine, then dried overMgSO4 and evaporated to dryness to produce 0.45 g of crude product. Thecrude material was subjected to column chromatography(eluent:CH₂Cl₂:MeOH (20:1)) to give the pure title compound (32) (0.03g, 5%). ¹H NMR (CDCl₃) 0.92 (t, 3H), 1.25–1.42 (m, 9H), 1.55–1.64 (m,2H), 1.75–1.82 (m, 2H), 2.10–2.23 (m, 2H), 2.24–2.31 (m, 2H), 2.67–2.77(m, 2H), 3.17–3.22 (m, 4H), 7.25–7.35 (m, 1H), 7.97–8.04 (m, 1H),8.08–8.13 (m, 1H).

Example 295-Nitro-2-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-benzoimidazole (33)(29MF04)

A 25 mL flask fitted with a condenser and a magnetic stirrer was chargedwith 1,2-diamino-4-nitrobenzen (0.259 g, 1.69 mmol) and4-(4-n-butylpiperidin-1-yl)-butyric acid methyl ester (4) (0.408 g, 1.69mmol) in 5 mL 4 M HCl. The reaction was refluxed for 24 h followed byaddition of 2.0 M NaOH to produce basic conditions, then stirred in roomtemperature for 1 h and extracted with ethyl acetate (5×50 mL). Thecombined organic phases were washed with 15 mL brine then dried overMgSO4 and evaporated to dryness to produce 0.27 g of a crude material.The crude material was subjected to column chromatography (eluent:CH₂Cl₂:MeOH (20:1)) to produce the final compound (122 mg). Thismaterial was isolated and dissolved in a 2.0 M HCl in ether solutionfollowed by evaporation to dryness to give the pure title compound (33)(80 mg, 10%). ¹H NMR (CD₃OD) 0.92(t, 3H), 1.34 (m, 6H), 1.55 (m, 3H),2.00 (d, 2H), 2.45 (m, 2H), 3.01 (t, 2H), 3.29–3.37 (dt, 4H), 3.64 (d,2H), 7.94 (d, 1H), 8.43 (dd, 1H), 8.65 (d, 1H).

Example 304-Hydroxy-2-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-benzoimidazole (34)(29MF07)

A 25 mL flask fitted with a condenser and magnetic stirrer was chargedwith 1,2-diamino-4-hydroxybenzene (0.177 g, 1.43 mmol) and4-(4-n-butylpiperidin-1-yl)-butyric acid methyl ester (4) (0.345 g, 1.43mmol) in 5 mL 4 M HCl. The reaction was refluxed for 20 h followed byaddition of 2.0 M NaOH to to produce basic conditions. The mixture wasevaporated to dryness on 10 mL silica and subjected to columnchromatography (eluent: CH₂Cl₂:MeOH (20:1)) to produce crude product(0.145 g). The crude was subjected to preparative HPLC (eluent: bufferA: 0.1% TFA; buffer B: 80% CH₃CN+0.1% TFA) and product isolated wasevaporated with 1.0 M TFA in ether to give the pure title compound 34(74 mg, 16%) as a trifluoroacetic acid salt. ¹H NMR(CD₃OD) 0.98(t, 3H),1.32–1.45 (m, 6H), 1.51–1.69 (m, 3H), 1.97–2.08 (d, 2H), 2.37–2.47 (m,2H), 2.95–3.12 (m, 2H), 3.26–3.41 (m, 4H), 3.58–3.3.72 (m, 2H),6.91–6.97 (d, 1H), 7.19–7.25 (d, 1H), 7.35–7.43 (t, 1H).

Example 31 2-(3-(4-n-Butylpiperidine)-1-yl-propyl)-1H-benzoimidazole(35) (21MF25)

A 25 mL flask fitted with a condenser and a magnetic stirrer was chargedwith 1,2-diaminobenzene (0.201 g, 18.6 mmol) and4-(4-n-butylpiperidin-1-yl)-butyric acid methyl ester (4) (0.50 g, 2.1mmol) in 6 mL 4 M HCl. The reaction was refluxed for 20 hours followedby addition of 2.0 M NaOH to to produce basic conditions. Theprecipitate was filtrated and dried under vacuum followed by columnchromatography (eluent: CH₂Cl₂:MeOH (10:1)) to produce the pure titlecompound 35 (0.40 g, 73%). mp 78–79° C., ¹H NMR(CDCl₃) 0.92 (t, 3H),1.33 (m, 6H), 1.50 (m, 3H), 1.80–1.95 (m, 2H), 2.0–2.15 (m, 2H),2.16–2.24 (m, 2H), 2.62–2.75 (m, 2H), 3.17–3.21 (m, 4H), 7.20–7.23 (m,2H), 7.52–7.59 (m, 2H).

Example 324-Methyl-2-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-benzoimidazole (36)(29MF08)

A 25 mL flask fitted with a condenser and a magnetic stirrer was chargedwith 1,2-diamino-3-methylbenzene (0.168 g, 1.37 mmol) and4-(4-n-butylpiperidin-1-yl)-butyric acid methyl ester (4) (0.331 g, 1.37mmol) in 5 mL 4 M HCl. The reaction was refluxed for 48 h followed byaddition of 4.0 M NaOH. The reaction mixture was extracted withdichloromethane (4×25 mL). The combined organic phases were dried overMgSO4 and evaporated to give 0.40 g of crude product. The crude materialwas subjected to column chromatography (eluent: CH₂Cl₂:MeOH (20:1)) andthe isolated product was evaporated to dryness with 1.0 M HCl in etherto give the pure title compound 36 (0.210 g, 44%). ¹H NMR(CD₃OD) 0.92(t, 3H), 1.33 (m, 6H), 1.54 (m, 3H), 1.99 (d, 2H), 2.43 (m, 2H), 2.65(m, 2H), 3.00 (m, 2H), 3.28 (m, 2H), 3.63 (m, 2H), 7.38 (d, 1H), 7.47(t, 1H), 7.59 (d, 1H).

Example 33 3-(2-(4-n-butylpiperidine)-1-yl-ethyl)-1H-indole (37)

A 25 mL flask fitted with a magnetic stirrer was charged4-n-butylpiperidine hydrochloride 3 (0.256 g, 1.4 mmol) and potassiumcarbonate (0.5 g, 3.6 mmol) in dioxane (5 mL). The mixture was stirredat room temperature for 2 h followed by addition of3-(2-bromoethyl)indole (0.30 g, 1.3 mmol) dissolved in dioxane (5 mL).The mixture was then stirred at 50° C. for 24 h. Addition of water (15mL) was followed by extraction with ethyl acetate (3×50 mL). Thecombined organic phases were dried over MgSO4 and evaporated to give1.02 g of crude product. The crude product was subjected to columnchromatography (Eluent: CH₂Cl₂:MeOH (20:1)) to give pure title compound37 (0.08 g, 21%). ¹H NMR(CDCl₃) 0.90(t, 3H), 1.25–1.49 (m, 9H),1.72–1.79 (m, 2H), 2.77 (t, 2H), 3.06 (t, 2H), 3.16 (d, 2H), 7.03 (s,1H), 7.11 (t, 1H), 7.19 (t, 1H), 7.36 (d, 1H), 7.61 (d, 1H), 8.09–8.16(s, 1H).

Example 34 (2-(4-Chloro-butan-1-one)-phenyl)-carbamic acid tert-butylester (38)

To a dry 100 mL one-necked flask fitted with condenser, a magneticstirrer and argon inlet was added 4-chlorobutanoyl chloride (624 mg, 44mmol) and bis(acetonitrile)dichloropalladium (34 mg) in 10 mL drytoluene. To the mixture was added (2-trimethylstannyl-phenyl)-carbamicacid tert-butyl ester (1.5 g, 42 mmol) (Bioorg. Med. Chem., 6:811(1998)) dissolved in 15 mL dry toluene. The mixture was then refluxedfor 1 h and then stirred in room temperature for 17 h. The reaction wasevaporated to dryness which produced a crude product (1.6 g) and thiswas subjected to column chromatography (eluent:heptane:EtOAc 10:1) togive the pure title compound 38 (1.15 g, 92%). ¹H NMR(CDCl₃) 1.52 (t,9H), 2.22 (m, 2H), 3.22 (t, 2H), 3.68 (t, 2H), 7.03 (t, 1H), 7.51 (t,1H), 7.91 (d, 1H), 8.48 (d, 1H), 10.90 (s, 1H).

Example 35 (2-(3-(4-n-butylpiperidine)-1-yl-propyl)-phenyl)-carbamicacid tert-butyl ester (39)

To a dry 5 mL flask fitted with a magnetic stirrer and argon inlet wasadded 38 (0.5 g, 1.7 mmol) and 4-n-butulpiperidine 3 (1.5 g, 10.6 mmol)and left stirring at 60° C. for 70 h. The crude reaction mixture wassubjected to column chromatography (eluent CH₂Cl₂:MeOH 20:1) to producethe pure compound 39 (0.49 g, 72%). ¹H NMR(CDCl₃) 0.87 (t, 3H),1.18–1.27 (m, 9H), 1.52 (s, 9H), 1.64 (m, 2H), 1.94 (m, 4H), 2.41 (t,2H), 2.91 (d, 2H), 3.03 (t, 2H), 7.00 (t, 1H), 7.49 (t, 1H), 7.91 (d,1H), 8.46 (d, 1H), 10.97 (s, 1H).

Example 36 3-(3-(4-n-Butylpiperidine)-1-yl-propyl)-1H-indazole (40)(39MF34)

Compound 39 (0.06 g, 0.15 mmol) dissolved 2 mL 4.0 M HCl in dioxane wasadded to a 5 mL flask and stirred at room temperature for 1 h. Themixture was evaporated to dryness and then redissolved in 1 mLconcentrated HCl and the temperature was adjusted to 0° C. with anice/water bath. To the cooled mixture was added sodium nitrite (0.010 g,0.15 mmol) dissolved in 2 mL water, and the reaction mixture wasmaintained at 0° C. for 1.5 h. followed by addition of tin dichloride(0.08 g, 0.36 mmol) dissolved in 2 mL concentrated HCl. After 1.5 h at0° C., crystals were formed. The crystals were filtered and washed withwater to produce the crude product (0.07 g). The crude product wassubjected to column chromatography (eluent:CH₂Cl₂:MeOH 20:1) to give thepure compound 40 (9.0 mg, 20%) ¹H NMR (CDCl₃) 0.88 (t, 3H), 1.19–1.33(m, 9H), 1.67 (d, 2H), 1.95 (t, 2H), 2.08 (m, 2H), 2.50 (t, 2H),2.93–3.20 (m, 4H), 7.12 (t, 1H), 7.36 (t, 1H), 7.43 (d, 1H), 7.71 (d,1H), 9.87–10.05 (s, 1H).

Example 37 3-(2-Chloro-ethoxy)-7-methyl-benzo[d]isoxazole (41)

1-Bromo-2-chloroethane (168 μl, 2.0 mmol) was added to 5 ml DMF in a 50ml flask. 7-Methyl-benzo[d]isoxazol-3-ol (298 mg, 2.0 mmol), potassiumcarbonate (276 mg, 2.0 mmol) and additional DMF (5 ml) were added andthe mixture was stirred for 12 h. Ethylacetate (50 ml) and H₂O (50 ml)were added. The two phases were separated and the aqueous phase wasextracted with ethylacetate. The combined organic phases were washedwith brine, dried over MgSO4 and evaporated to dryness to give 420 mg ofthe crude product. The crude product was subjected to columnchromatography (0–5% methanol in dichloromethane) to give the pure titlecompound 41 (290 mg, 70%). ¹H NMR (CDCl₃) 2.5 (s, 3H), 3.9 (t, 2H), 4.7(t, 2H), 7.2 (t, 1H), 7.3 (d, 1H), 7.5 (d, 2H).

Example 38 3-(2-(4-n-Butylpiperidine)-ethoxy)-7-methyl-benzo[d]isoxazole(42) (35AKU-41)

Compound 41 (294 mg, 1.4 mmol) was dissolved in DMF (5 ml) in a 50 mlflask followed by addition of a mixture of 4-n-butyl-piperidine (284 mg;1.6 mmol) and potassium carbonate (442 mg; 3.2 mmol) dissolved in DMF(15 ml). The mixture was stirred for 2 days at 80° C. Ethylacetate (50ml) and H₂O (50 ml) were added, the phases were separated, and theaqueous phase was extracted with ethylacetate (3×50 ml). The combinedorganic phases were washed with brine, dried over MgSO4 and evaporatedto dryness to produce the crude product (454 mg). The crude product wassubjected to column chromatography (0–5% methanol in dichloromethane) toproduce the pure title compound 42 (131 mg, 30%). The oxalate salt wasprepared from oxalic acid (1.1 eq.) in methanol/diethylether. ¹H NMR(CDCl₃) 0.9 (t, 3H), 1.2–1.3 (m, 9H), 1.7 (d, 2H), 2.1 (t, 2H), 2.5 (s,3H), 2.9 (t, 2H), 3.0 (d, 2H), 4.6 (t, 2H), 7.15 (t, 1H), 7.3 (d, 1H),7.45 (d, 1H).

Example 39 1-(3-(4-Methylpiperidine)-1-yl-propyl)-1H-indazole (43)(46RO13.48)

Solid K₂CO₃ (70 mg, 0.5 mmol) was added to a mixture of7-bromo-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole (96 mg, 0.4mmol) and 4-methylpiperidine (30 mg, 0.3 mmol) in CH₃CN (2 ml). Theresulting slurry was stirred at 50° C. for 48 h and then cooled toambient temperature. The slurry was then poured into water (10 ml) andworked up as follows: extraction with ethyl acetate (3×10 ml), washingof the collected organic phases sequentially with water (3×5 mL) andbrine, followed by drying over MgSO4 and removal of the solvent byrotary evaporation. The residue was purified on ISOLUTE SCX to givecompound 43 (25 mg, 24%). Oxalate-salt was prepared from oxalic acid(1.1 eq.) in methanol/diethylether. ¹H NMR (CD₃OD) δ 0.9 (t, 3H), 1.2(m, 2H), 1.6 (m, 1H), 1.8 (d, 2H), 2.15 (m, 2H), 2.8 (m, 2H), 3.0 (m,2H), 3.4 (m, 2H), 4.45 (t, 2H), 7.1 (t, 1H), 7.35 (t, 1H), 7.5 (d, 1H),7.7 (d, 1H), 8.0 (s, 1H).

Example 40 1-(3-(4-Pentylpiperidine)-1-yl-propyl)-1H-indazole (44)(46RO13.57)

Solid K₂CO₃ (35 mg, 0.25 mmol) was added to a mixture of7-bromo-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole 48 mg, 0.4mmol) and 4-pentylpiperidine (23 mg, 0.15 mmol) in CH₃CN (2 ml). Theresulting slurry was stirred at 50° C. for 48 h and then cooled toambient temperature. The slurry was then poured into water (10 ml) andworked up as follows: extraction with ethyl acetate (3×10 ml), washingof the collected organic phases sequentially with water (3×5 ml) andbrine, followed by drying over MgSO4 and removal of the solvent byrotary evaporation. The residue was purified on ISOLUTE SCX to givecompound 44 (25 mg, 40%). Oxalate-salt was prepared from oxalic acid(1.1 eq.) in methanol/diethylether. ¹H NMR (CD₃OD) δ 0.9 (t, 3H), 1.2(m, 12H), 1.6 (m, 1H), 1.8 (d, 2H), 2.15 (m, 2H), 2.8 (m, 2H), 3.0 (m,2H), 3.4 (m, 2H), 4.45 (t, 2H), 7.1 (t, 1H), 7.35 (t, 1H), 7.5 (d, 1H),7.7 (d, 1H), 8.0 (s, 1H).

Example 41 1-(3-(4-Propylpiperidine)-1-yl-propyl)-1H-indazole (45)(46RO13.55LH)

Solid K₂CO₃ (35 mg, 0.25 mmol) was added to a mixture of7-bromo-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole (48 mg, 0.2mmol) and 4-propylpiperidine (19 mg, 0.15 mmol) in CH₃CN (2 ml). Theresulting slurry was stirred at 50° C. for 48 h and then cooled toambient temperature. The slurry was then poured into water (10 ml) andworked up as follows: extraction with ethyl acetate (3×10 ml), washingof the collected organic phases sequentially with water (3×5 ml) andbrine, followed by drying over MgSO4 and removal of the solvent byrotary evaporation. The residue was purified on ISOLUTE SCX to givetitle compound 45 (16 mg, 28%). Oxalate-salt was prepared from oxalicacid (1.1 eq.) in methanol/diethylether. ¹H NMR (CD₃OD) δ 0.9 (t, 3H),1.2 (m, 6H), 1.6 (m, 1H), 1.8 (d, 2H), 2.15 (m, 2H), 2.8 (m, 2H), 3.0(m, 2H), 3.4 (m, 2H), 4.45 (t, 2H), 7.1 (t, 1H), 7.35 (t, 1H), 7.5 (d,1H), 7.7 (d, 1H), 8.0 (s, 1H).

Example 42 1-(3-(4-(3-Methyl-butyl)-piperidine)-1-yl-propyl)-1H-indazole(46) (46RO13.58)

Solid K₂CO₃ (35 mg, 0.25 mmol) was added to a mixture of7-bromo-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole (48 mg, 0.2mmol) and 4-(3-methyl-butyl)-piperidine (23 mg, 0.15 mmol) in CH₃CN (2ml). The resulting slurry was stirred at 50° C. for 48 h and then cooledto ambient temperature. The slurry was then poured into water (10 ml)and worked up as follows: extraction with ethyl acetate (3×10 ml),washing of the collected organic phases sequentially with water (3×5 ml)and brine, followed by drying over MgSO4 and removal of the solvent byrotary evaporation. The residue was purified on ISOLUTE SCX to givetitle compound 46 (18 mg, 30%). Oxalate-salt was prepared from oxalicacid (1.1 eq.) in methanol/diethylether. ¹H NMR (CD₃OD) δ 0.9 (t, 6H),1.2–1.5 (m, 8H), 1.8 (d, 2H), 2.15 (m, 2H), 2.8 (m, 2H), 3.0 (m, 2H),3.4 (m, 2H), 4.45 (t, 2H), 7.1 (t, 1H), 7.35 (t, 1H), 7.5 (d, 1H), 7.7(d, 1H), 8.0 (s, 1H).

Example 43 1-(3-(4-Pentylidene-piperidine)-1-yl-propyl)-1H-indazole (47)(46RO13.46)

Solid K₂CO₃ (35 mg, 0.25 mmol) was added to a mixture of7-bromo-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole (48 mg, 0.2mmol) and 4-Pentylidene-piperidine (23 mg, 0.15 mmol) in CH₃CN (2 ml).The resulting slurry was stirred at 50° C. for 48 h and then cooled toambient temperature. The slurry was poured into water (10 ml) and workedup as follows: extraction with ethyl acetate (3×10 ml), washing of thecollected organic phases sequentially with water (3×5 ml) and brine,followed by drying over MgSO4 and removal of the solvent by rotaryevaporation. The residue was purified on ISOLUTE SCX to give the titlecompound 47 (3 mg, 5%). Oxalate-salt was prepared from oxalic acid (1.1eq.) in methanol/diethylether. ¹H NMR (CD₃OD) δ 0.9 (t, 3H), 1.3 (m,4H), 2.0 (m, 2H), 2.3 (m, 3H), 2.35 (d, 2H), 2.7 (m, 2H), 3.1 (m, 3H),3.4 (m, 2H), 4.45 (t, 2H), 5.3 (m, 1H) 7.1 (t, 1H), 7.35 (t, 1H), 7.5(d, 1H), 7.7 (d, 1H), 8.0 (s, 1H).

Example 44 1-(3-(4-Propylidene-piperidine)-1-yl-propyl)-1H-indazole (48)(46RO13.45)

Solid K₂CO₃ (35 mg, 0.25 mmol) was added to a mixture of7-bromo-1-(3-(4-n-butylpiperidine)-1-yl-propyl)-1H-indole (48 mg, 0.2mmol) and 4-Propylidene-piperidine (18 mg, 0.15 mmol) in CH₃CN (2 ml).The resulting slurry was stirred at 50° C. for 48 h and then cooled toambient temperature. The slurry was poured into water (10 ml) and workedup as follows: extraction with ethyl acetate (3×10 ml), washing of thecollected organic phases sequentially with water (3×5 ml) and brine,followed by drying over MgSO4 and removal of the solvent by rotaryevaporation. The residue was purified on ISOLUTE SCX to give the titlecompound 48 (10 mg, 25%). Oxalate-salt was prepared from oxalic acid(1.1 eq.) in methanol/diethylether. ¹H NMR (CD₃OD) δ 0.9 (t, 3H), 2.0(t, 2H), 2.4 (m, 6H), 3.1 (m, 4H), 3.4 (m, 2H), 4.45 (t, 2H), 5.35 (t,1H), 7.1 (t, 1H), 7.35 (t, 1H), 7.5 (d, 1H), 7.7 (d, 1H), 8.0 (s, 1H).

Example 45 1-Benzo[b]thiophen-2-yl-4-(4-butylpiperidin-1-yl)-butan-1-one(49) (45NK99/oxalate)

n-BuLi in heptanes (0.77 ml, 1.0 mmol, 1.3M) was added dropwise tobenzo[b]thiophene (134 mg, 1.0 mmol) in THF (4 ml) at −78° C. underargon. The reaction mixture was stirred at −78° C. for 15 min, then4-(4-butyl-piperidin-1-yl)-N-methoxy-N-methyl-butyramide (135 mg, 0.5mmol) in THF (1 ml) was added. The reaction was stirred at −78° C. for30 min, then NH₄Cl (sat. aq., 1 ml) was added and the reaction warmed toroom temperature. The product was extracted with ethyl acetate (2×20 ml)and the organic layer was washed with water (10 ml), dried (K₂CO₃),filtered and concentrated in vacuo. The product was purified by columnchromatography (0–25% ethyl acetate in heptanes+0.1% Et₃N). Yield 94 mg(55%). The oxalate salt was formed by addition of oxalic acid in diethylether:methanol (10:1) to give a white precipitate that was filtered anddried. ¹H NMR (DMSO): δ 0.91 (t, 3H), 1.24–1.56 (m, 9H), 1.87 (br. d,2H), 2.08 (m, 2H), 2.93 (m, 2H), 3.14 (m, 2H), 3.24 (m, 2H), 3.47 (m,2H), 7.46–7.59 (m, 2H), 8.05 (m, 2H), 8.36 (s, 1H).

Example 464-(4-Butylpiperidin-1-yl)-1-(3-methyl-benzofuran-2-yl)-butan-1-one (50)(45NK100/oxalate)

n-BuLi in heptanes (0.85 ml, 1.1 mmol, 1.3M) was added drop wise to3-methylbenzofuran (132 mg, 1.0 mmol) in THF (4 ml) at −78° C. underargon. The reaction mixture was stirred at −78° C. for 20 min, then4-(4-butyl-piperidin-1-yl)-N-methoxy-N-methyl-butyramide (135 mg, 0.5mmol) in THF (1 ml) was added. The reaction was stirred at −78° C. for45 min, then NH₄Cl (sat. aq., 1 ml) was added and the reaction warmed toroom temperature. The product was extracted with ethyl acetate (2×20 ml)and the organic layer was washed with water (10 ml), dried (K₂CO₃),filtered and concentrated in vacuo. The product was purified by columnchromatography (0–20% ethyl acetate in heptanes+0.1% Et₃N). Yield 38 mg(22%). The oxalate salt was formed by addition of oxalic acid in diethylether:methanol (10:1) to give a white precipitate that was filtered anddried. ¹H NMR (CD₃OD): δ 0.91 (t, 3H), 1.32 (m, 6H), 1.42–1.64 (m, 3H),1.89 (br. d, 2H), 2.15 (tt, 2H), 2.58 (s, 3H) 2.96 (m, 2H), 3.17 (m,4H), 3.60 (m, 2H), 7.33 (m, 1H), 7.52 (m, 2H), 7.71 (m, 1H).

Example 474-(4-Butylpiperidin-1-yl)-4-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-butan-1-one(51) (45NK105)

n-BuLi in heptanes (0.50 ml, 0.8 mmol, 1.6M) was added drop wise to5-fluoro-3-methyl-benzo[b]thiophene (166 mg, 1.0 mmol) in THF (4 ml) at−40° C. under argon. The reaction mixture was stirred at −40° C. for 40min then 4-(4-butyl-piperidin-1-yl)-N-methoxy-N-methyl-butyramide (135mg, 0.5 mmol) in THF (1 ml) was added. The reaction was stirred at −40°C. for 30 min, then NH₄Cl (sat. aq., 1 ml) was added and the reactionwarmed to room temperature. The product was extracted with ethyl acetate(2×20 ml) and the organic layer was washed with water (10 ml), dried(K₂CO₃), filtered and concentrated in vacuo. The product was purified ona Isco CombiFlash Sq 16× (4.1 g silica column, eluting heptanes (5 min),0–15% ethyl acetate in heptanes (20 min), 15% ethyl acetate in heptanes(15 min), all solvents+0.1% Et₃N). Yield 39 mg (21%). The hydrochloridesalt was formed by addition of HCl (4M in dioxane) and recrystallisedfrom methanol-diethyl ether to give a white precipitate that wasfiltered and dried. ¹H NMR (free base, CDCl₃): δ 0.87 (t, 3H), 1.10–1.35(m, 9H), 1.62 (br. d, 2H), 1.96 (m, 4H), 2.42 (t, 2H), 2.71 (s, 3H),2.93 (m, 4H), 7.34 (dt, 1H), 7.49 (dd, 1H), 7.76 (dd, 1H).

Example 48 1-Benzofuran-2-yl-4-(4-butylpiperidin-1-yl)-butan-1-one (52)(45NK106)

n-BuLi in heptanes (0.50 ml, 0.8 mmol, 1.6M) was added drop wise tobenzofuran (118 mg, 1.0 mmol) in THF (4 ml) at −40° C. under argon. Thereaction mixture was stirred at −40° C. for 40 min, then4-(4-butylpiperidin-1-yl)-N-methoxy-N-methyl-butyramide (135 mg, 0.5mmol) in THF (1 ml) was added. The reaction was stirred at −40° C. for30 min, then NH₄Cl (sat. aq., 1 ml) was added and the reaction warmed toroom temperature. The product was extracted with ethyl acetate (2×20 ml)and the organic layer was washed with water (10 ml), dried (K₂CO₃),filtered and concentrated in vacuo. The product was purified on a IscoCombiFlash Sq 16× (4.1 g silica column, eluting heptanes (5 min), 0–15%ethyl acetate in heptanes (20 min), 15% ethyl acetate in heptanes (15min), all solvents+0.1% Et₃N). Yield 61 mg (50%). The hydrochloride saltwas formed by addition of HCl (4M in dioxane) and recrystallised frommethanol-diethyl ether to give a white precipitate that was filtered anddried. ¹H NMR (free base, CDCl₃): δ 0.87 (t, 3H), 1.10–1.30 (m, 9H),1.59 (br. d, 2H), 1.93 (m, 2H), 1.99 (tt, 2H), 2.40 (t, 2H), 2.87 (m,2H), 2.96 (t, 2H), 7.30 (m, 1H), 7.45 (m, 1H), 7.48 (m, 1H), 7.57 (m,1H), 7.69 (m, 1H).

Example 491-(3-Bromo-benzo[b]thiophen-2-yl)-4-(4-butylpiperidin-1-yl)-butan-1-one(53) (45NK108)

t-BuLi in pentanes (0.48 ml, 0.8 mmol, 1.7M) was added drop wise to3-bromo-benzo[b]thiophene (213 mg, 1.0 mmol) in THF (4 ml) at −78° C.under argon. The reaction mixture was stirred at −78° C. for 40 min,then 4-(4-butylpiperidin-1-yl)-N-methoxy-N-methyl-butyramide (135 mg,0.5 mmol) in THF (1 ml) was added. The reaction was stirred at −78° C.for 30 min, then NH₄Cl (sat. aq., 1 ml) was added and the reactionwarmed to room temperature. The product was extracted with ethyl acetate(2×20 ml) and the organic layer was washed with water (10 ml), dried(K₂CO₃), filtered and concentrated in vacuo. The product was purified ona Isco CombiFlash Sq 16× (4.1 g silica column, eluting heptanes (5 min),0–15% ethyl acetate in heptanes (20 min), 15% ethyl acetate in heptanes(15 min), all solvents+0.1% Et₃N). Yield 18 mg (4%). The hydrochloridesalt was formed by addition of HCl (4M in dioxane) and recrystallisedfrom methanol-diethyl ether to give a white precipitate that wasfiltered and dried. ¹H NMR (free base, CDCl₃): δ 0.88 (t, 3H), 1.12–1.28(m, 9H), 1.62 (br. d, 2H), 1.94 (m, 2H), 2.02 (tt, 2H), 2.45 (t, 2H),2.92 (br. d, 2H), 31.8 (t, 2H), 7.51 (m, 2H), 7.83 (m, 1H), 7.98 (m,1H).

Example 50 1-(3-Benzo[b]thiophen-2-yl-propyl)-4-butylpiperidine (54)(45NK124)

n-BuLi in heptanes (0.75 ml, 1.2 mmol, 1.6M) was added drop wise tobenzo[b]thiophene (134 mg, 1.0 mmol) in THF (4 ml) at −5° C. underargon. The reaction mixture was stirred at −5° C. for 15 min, then1-chloro-3-iodopropane (151 μl, 1.2 mmol) and copper (I) iodide (19 mg,0.1 mmol) were added. The reaction was stirred at −5° C. for 1 h, thenat room temperature for 0.5 h. Water (5 ml) was added, the product wasextracted with diethyl ether (2×10 ml) and the organic layer was dried(K₂CO₃), filtered and concentrated in vacuo. The product was purified bycolumn chromatography (0–2% ethyl acetate in heptanes) to give2-(3-chloro-propyl)-benzo[b]thiophene (93 mg, 44%). ¹H NMR (CDCl₃): δ2.22 (tt, 2H), 3.10 (dt, 2H), 3.61 (t, 2H), 7.06 (m, 1H), 7.30 (m, 2H),7.69 (m, 1H), 7.78 (m, 1H). 2-(3-Chloro-propyl)-benzo[b]thiophene (53mg, 0.25 mmol), 4-butylpiperidine (36 mg, 0.25 mmol), sodium iodide (75mg, 0.5 mmol) and sodium carbonate (53 mg, 0.5 mmol) in acetonitrile (2ml) were shaken at 80° C. for 18 h, then the reaction was cooled to roomtemperature. Water (5 ml) was added and the product was extracted withethyl acetate (2×10 ml), dried (K₂CO₃), filtered and concentrated invacuo. The product was purified by column chromatography (0–15% ethylacetate in heptanes+0.1% Et₃N) to yield the title compound 54. Yield 29mg (37%). The hydrochloride salt was formed by addition of HCl (4M indioxane) and recrystallised from methanol-diethyl ether to give a whiteprecipitate that was filtered and dried. ¹H NMR (CD₃OD): δ 0.91 (t, 3H),1.32 (m, 6H), 1.39 (m, 2H), 1.55 (m, 1H), 1.96 (br. d, 2H), 2.19 (tt,2H), 2.93 (m, 2H), 3.04 (t, 2H), 3.14 (m, 2H), 3.53 (m, 2H), 7.14 (br.s, 1H), 7.26 (m, 1H), 7.31 (m, 1H), 7.68 (m, 1H), 7.77 (m, 1H).

Example 51 1-(3-Benzofuran-2-yl-propyl)-4-butylpiperidine (55) (56NK03)

n-BuLi in heptanes (1.5 ml, 2.4 mmol, 1.6M) was added drop wise tobenzofuran (236 mg, 2.0 mmol) in THF (5 ml) at −20° C. under argon. Thereaction mixture was stirred at −15° C. for 30 min, then1-chloro-3-iodopropane (322 μl, 3.0 mmol) and copper (I) iodide (38 mg,0.2 mmol) were added. The reaction was stirred at −15° C. for 1 h, thenNH₄Cl (sat. aq., 5 ml) was added. The product was extracted with diethylether (2×30 ml) and the organic layer was washed with brine (10 ml),dried (K₂CO₃), filtered and concentrated in vacuo. The product waspurified by column chromatography (0–1% diethyl ether in heptanes) togive 2-(3-chloro-propyl)-benzofuran (101 mg, 26%). ¹H NMR (CDCl₃): δ2.23 (tt, 2H), 2.97 (dt, 2H), 3.62 (t, 2H), 6.45 (q, 1H), 7.21 (m, 2H),7.42 (m, 1H), 7.50 (m, 1H).

2-(3-Chloro-propyl)-benzofuran (101 mg, 0.52 mmol), 4-butylpiperidine(74 mg, 0.52 mmol), sodium iodide (156 mg, 1.04 mmol) and sodiumcarbonate (110 mg, 1.04 mmol) in acetonitrile (2 ml) were shaken at 80°C. for 18 h, then the reaction was cooled to room temperature. Water (1ml) was added, the product was extracted with ethyl acetate (2×2 ml),and the organic layer loaded onto a Varian SCX ion exchange column. Thecolumn was washed with methanol (2 column volumes) and the product waseluted from the column using 10% ammonium hydroxide in methanol (2column volumes). The solute was concentrated in vacuo, dissolved up inacetone, dried (K₂CO₃) and concentrated in vacuo. The product waspurified by column chromatography (0–12% ethyl acetate in heptanes+0.1%Et₃N) to yield the title compound 55. Yield 86 mg (55%). Thehydrochloride salt was formed by addition of HCl (4M in dioxane) andrecrystallised from methanol-diethyl ether to give a white flaky solidthat was filtered and dried. ¹H NMR (CD₃OD): δ 0.90 (t, 3H), 1.30 (m,6H), 1.48 (m, 3H), 1.95 (br. d, 2H), 2.21 (m, 4H), 2.91 (m, 4H), 3.16(m, 2H), 3.55 (br. d, 2H), 6.57 (s, 1H), 7.17 (m, 2H), 7.38 (m, 2H),7.48 (m, 1H).

Example 52 4-Butyl-1-[3-(3-methyl-benzofuran-2-yl)-propyl]-piperidine(56) (56NK04)

n-BuLi in heptanes (1.5 ml, 2.4 mmol, 1.6M) was added drop wise to3-methylbenzofuran (264 mg, 2.0 mmol) in THF (5 ml) at −20° C. underargon. The reaction mixture was stirred at −15° C. for 30 min, then1-chloro-3-iodopropane (322 μl, 3.0 mmol) and copper (I) iodide (38 mg,0.2 mmol) were added. The reaction was stirred at −15° C. for 1 h, thenNH₄Cl (sat'd aq., 5 ml) was added. The product was extracted withdiethyl ether (2×30 ml) and the organic layer was washed with brine, (10ml) dried (K₂CO₃), filtered and concentrated in vacuo. The product waspurified by column chromatography (0–1% diethyl ether in heptanes) togive 2-(3-chloro-propyl)-3-methylbenzofuran (25 mg, 6%). ¹H NMR (CDCl₃):δ 2.19 (tt, 2H), 2.22 (s, 3H), 2.94 (t, 2H), 3.57 (t, 2H), 7.22 (m, 2H),7.38 (m, 1H), 7.44 (m, 1H).

2-(3-Chloro-propyl)-3-methylbenzofuran (25 mg, 0.12 mmol),4-butylpiperidine (17 mg, 0.12 mmol), sodium iodide (35 mg, 0.24 mmol)and sodium carbonate (25 mg, 0.24 mmol) in acetonitrile (2 ml) wereshaken at 80° C. for 18 h, then the reaction was cooled to roomtemperature. Water (1 ml) was added, the product was extracted withethyl acetate (2×2 ml) and the organic layer loaded onto a Varian SCXion exchange column. The column was washed with methanol (2 columnvolumes), then the product was eluted from the column using 10% ammoniumhydroxide in methanol (2 column volumes). The solute was concentrated invacuo, dissolved in acetone, dried (K₂CO₃) and concentrated in vacuo.The product was purified by column chromatography (0–12% ethyl acetatein heptanes+0.1% Et₃N) to yield the title compound 56. Yield 14 mg(38%). The hydrochloride salt was formed by addition of HCl (4M indioxane) and recrystallised from methanol-diethyl ether to give a whitesolid that was filtered and dried. ¹H NMR (CD₃OD): δ 0.91 (t, 3H),1.28–1.45 (m, 8H), 1.55 (m, 1H), 1.96 (br. d, 2H), 2.17 (m, 2H), 2.22(s, 3H), 2.89 (t, 2H), 2.94 (m, 2H), 3.14 (m, 2H), 3.54 (m, 2H), 7.20(m, 2H), 7.34 (m, 1H), 7.45 (m, 1H).

Example 534-Butyl-1-[3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-propyl]-piperidine(57) (56NK05)

n-BuLi in heptanes (1.5 ml, 2.4 mmol, 1.6M) was added drop wise to5-fluoro-3-methyl-benzo[b]thiophene (332 mg, 2.0 mmol) in THF (5 ml) at−20° C. under argon. The reaction mixture was stirred at −15° C. for 30min, then 1-chloro-3-iodopropane (322 μl, 3.0 mmol) and copper (1)iodide (38 mg, 0.2 mmol) were added. The reaction was stirred at −15° C.for 1 h, then NH₄Cl (sat'd aq., 5 ml) was added. The product wasextracted with diethyl ether (2×30 ml) and the organic layer was washedwith brine (10 ml), dried (K₂CO₃), filtered and concentrated in vacuo.The product was purified by column chromatography (0–1% diethyl ether inheptanes) to give2-(3-chloro-propyl)-5-fluoro-3-methyl-benzo[b]thiophene (180 mg, 37%).¹H NMR (CDCl₃): δ 2.19 (tt, 2H), 2.22 (s, 3H), 2.94 (t, 2H), 3.57 (t,2H), 7.04 (dt, 1H), 7.28 (dd, 1H), 7.66 (dd, 1H).

2-(3-Chloro-propyl)-5-fluoro-3-methyl-benzo[b]thiophene (180 mg, 0.74mmol), 4-butylpiperidine (212 mg, 0.74 mmol), sodium iodide (225 mg,1.48 mmol) and sodium carbonate (159 mg, 1.48 mmol) in acetonitrile (2ml) were shaken at 80° C. for 18 h, then the reaction was cooled to roomtemperature. Water (1 ml) was added, the product was extracted withethyl acetate (2×2 ml), and the organic layer loaded onto a Varian SCXion exchange column. The column was washed with methanol (2 columnvolumes), then the product was eluted from the column using 10% ammoniumhydroxide in methanol (2 column volumes). The solute was concentrated invacuo, dissolved in acetone, dried (K₂CO₃) and concentrated in vacuo.The product was purified by column chromatography (0–12% ethyl acetatein heptanes+0.1% Et₃N) to yield the title compound 57. Yield 185 mg(72%). The hydrochloride salt was formed by addition of HCl (4M indioxane) and recrystallised from methanol-diethyl ether to give whitecrystals that were filtered and dried. ¹H NMR (CD₃OD): δ 0.90 (t, 3H),1.31 (m, 6H), 1.37–1.62 (m, 3H), 1.94 (br. d, 2H), 2.15 (m, 2H), 2.31(s, 3H), 2.92 (br. t, 2H), 3.01 (tm, 2H), 3.14 (m, 2H), 3.54 (br. d,2H), 7.06 (dt, 2H), 7.34 (dd, 1H), 7.73 (dd, 1H).

Example 54 2-(3-Iodo-propyl)-benzo[b]thiophene (58)

A mixture of 2-(3-Chloro-propyl)-benzo[b]thiophene (902 mg, 4.28 mmol)and sodium iodide (1.29 g, 8.6 mmol) was heated to 50° C. in acetone (5ml) for 72 h, then cooled to room temperature. Aqueous sodiumthiosulphate (1 M, 10 ml) was added and the product was extracted withdiethyl ether (2×20 ml). The organic layer was dried (K₂CO₃), filteredand concentrated in vacuo to give a white solid that was filteredthrough Celite and eluted with heptanes. The filtrate was concentratedin vacuo to give a white solid. Yield 1.038 g (80%). ¹H NMR (CDCl₃): δ2.24 (tt, 2H), 3.04 (dt, 2H), 3.27 (t, 2H), 7.07 (q, 1H), 7.28 (m, 2H),7.68 (m, 1H), 7.77 (m, 1H).

General Procedure for the Alkylation of Amines.

2-(3-Iodo-propyl)-benzo[b]thiophene (33 mg, 0.11 mmol) in DCM (240 μl)was added to the amine (0.10 mmol) in DCM (200 μl) and the reaction wasshaken at room temperature for 18 h. DCM (1 ml) was added followed bymacroporous triethylammonium methylpolystyrene carbonate (50 mg, 3.06mmol/g loading, Argonaut Technologies) and the reaction was shaken atroom temperature for 1 h. Polystyrene methylisocyanate (60 mg, 1.25mmol/g, Argonaut Technologies) was added and the reaction was shaken atroom temperature for 2 h. The reaction was than loaded onto a Varian SCXion exchange column. The column was washed with methanol (2 columnvolumes) and the product was eluted from the column using 10% ammoniumhydroxide in methanol (2 column volumes). The solute was concentrated invacuo, dissolved in acetone, dried (K₂CO₃) and concentrated in vacuo.

Example 55 1-(3-Benzo[b]thiophen-2-yl-propyl)-4-methylpiperidine (59)(56NK38)

The reaction was carried out according to the general procedure using4-methyl-piperidine (17 mg, 0.10 mmol) to yield 14 mg (53%) of1-(3-benzo[b]thiophen-2-yl-propyl)-4-methylpiperidine. ¹H NMR (CD₃OD): δ0.92 (d, 3H), 1.27 (m, 2H), 1.34 (m, 1H), 1.63 (m, 2H), 1.94 (m, 4H),2.40 (t, 2H), 2.91 (m, 4H), 7.00 (d, 1H), 7.28 (m, 2H), 7.66 (m, 1H),7.76 (m, 1H).

Example 56 1-(3-Benzo[b]thiophen-2-yl-propyl)-4-benzylpiperidine (60)(56NK40)

The reaction was carried out according to the general procedure using4-benzyl-piperidine (17 mg, 0.10 mmol) to yield 16 mg (45%) of1-(3-benzo[b]thiophen-2-yl-propyl)-4-benzyl-piperidine. ¹H NMR (CD₃OD):δ 1.29 (m, 2H), 1.47–1.67 (m, 4H), 1.92 (m, 4H), 2.38 (m, 2H), 2.52 (m,3H), 2.88 (m, 4H), 7.03 (m, 1H), 7.10–7.15 (m, 3H), 7.18–7.28 (m, 4H),7.63 (m, 1H), 7.72 (m, 1H).

Example 571-(3-Benzo[b]thiophen-2-yl-propyl)-4-(2-methoxy-phenyl)-piperidine (61)(56NK42)

The reaction was carried out according to the general procedure using4-(2-methoxy-phenyl)-piperidine (17 mg, 0.10 mmol) to yield 17 mg (47%)of 1-(3-benzo[b]thiophen-2-yl-propyl)-4-(2-methoxy-phenyl)-piperidine.¹H NMR (CD₃OD): δ 1.77 (m, 4H), 1.98 (m, 2H), 2.10 (m, 2H), 2.46 (m,2H), 2.94 (m, 3H), 3.04 (m, 2H), 3.79 (s, 3H), 6.88 (m, 2H), 7.06 (br.s, 1H), 7.13 (m, 2H), 7.26 (m, 2H), 7.65 (m, 1H), 7.73 (m, 1H).

Example 58 2-(3-Bromopropyl)-2H-benzotriazole (35AKU-17-2) (62)

To a solution of 1,3-dibromopropane (510 μl, 5.0 mmol) indimethylformamide (10 ml) was added benzotriazole (600 mg, 5.0 mmol) andKOH (430 mg, 7.7 mmol). After stirring for 20 h at room temp, water (10ml) and ethyl acetate (10 ml) were added. The phases were separated andthe aqueous phase was re-extracted with ethyl acetate (3×15 ml). Thecombined organic phases were dried over MgSO4 and concentrated in vacuo,giving 1.44 g of the crude material. The crude product was purified byflash chromatography (0–10% methanol in DCM), yielding 274 mg (23%) ofthe title compound 62. TLC (5% methanol in DCM): R_(f)=0.7. ¹H-NMR (400MHz, CDCl₃): δ=7.88–7.83 (2H, m); 7.41–7.36 (2H, m); 4.91 (2H, t); 3.44(2H, t); 2.66 (2H, m).

Example 59 2-[3-(4-Butylpiperidin-1-yl)-propyl]-2H-benzotriazole (63)(35AKU-18)

To a solution of 2-(3-bromopropyl)-2H-benzotriazole (274 mg, 1.14 mmol)in dimethylformamide (5 ml) was added a solution of 4-butylpiperidine(142 mg, 1.0 mmol) and KOH (125 mg, 2.2 mmol) in dimethylformamide (5ml). The mixture was stirred for 20 h at room temp., and ethyl acetate(10 ml) and water (10 ml) were then added. The phases were separated andthe aqueous phase was re-extracted with ethyl acetate (3×20 ml). Thecombined organic phases were dried over MgSO4 and concentrated in vacuoto produce 383 mg of the crude material. The crude product was purifiedby flash chromatography (0–10% methanol in DCM) yielding 232 mg (77%) ofthe title compound 63. The oxalate-salt was prepared from oxalic acid(1.1 eq.) in diethyl ether. TLC (10% methanol in DCM): R_(f)=0.4.HPLC-MS (Method A): M⁺=301.2 (UV/MS(%)=100/89). ¹H-NMR (400 MHz, CDCl₃):δ=7.86 (2H, m); 7.37 (2H, m); 4.78 (2H, t); 2.93 (2H, d); 2.45 (2H, d);2.34 (2H, m); 1.94 (2H, t); 1.61 (2H, d); 1.32–1.13 (9H, m); 0.88 (3H,t).

Example 60 1-(3-Bromopropyl)-1H-benzotriazole (35AKU-17-1) (64)

To a solution of 1,3-dibromopropane (510 μl, 5.0 mmol) indimethylformamide (10 ml) was added benzotriazole (600 mg, 5.0 mmol) andKOH (430 mg, 7.7 mmol). After stirring for 20 h at room temp., water (15ml) and ethyl acetate (15 ml) were added. The phases were separated andthe aqueous phase was re-extracted with ethyl acetate (3×20 ml). Thecombined organic phases were dried over MgSO4 and concentrated, giving1.44 g of the crude product. The crude product was purified by flashchromatography (0–10% methanol in DCM) yielding 705 mg (59%) of thetitle compound 64. TLC (5% methanol in DCM): R_(f)=0.4. HPLC-MS (MethodA): M⁺=239.9 (UV/MS(%)=52/58).

Example 61 1-[3-(4-Butylpiperidin-1-yl)-propyl]-1H-benzotriazole (65)(35AKU-19)

To a solution of 1-(3-bromopropyl)-1H-benzotriazole (705 mg, 1.6 mmol)in dimethylformamide (5 ml) was added a solution of 4-butylpiperidine(140 mg, 1.0 mmol) and KOH (240 mg, 4.3 mmol) dissolved indimethylformamide (5 ml). The mixture was stirred for 20 h at room temp.Ethyl acetate (10 ml) and water (10 ml) were then added. The phases wereseparated and the aqueous phase was re-extracted with ethyl acetate(3×15 ml). The combined organic phases were washed with brine, driedover MgSO4 and evaporated to dryness, giving 776 mg of the crudematerial. The crude product was purified by flash chromatography (0–10%methanol in DCM) yielding 146 mg (49%) of the title compound 65. Theoxalate-salt was prepared from oxalic acid (1.1 eq.) in diethyl ether.TLC (10% methanol in DCM): R_(f)=0.4. HPLC-MS (Method A): M⁺=301.2(UV/MS(%)=100/99). ¹H-NMR (400 MHz, CDCl₃): δ=8.05 (1H, m); 7.62–7.33(3H, m); 4.71 (2H, t); 2.85 (2H, d); 2.34 (2H, m); 2.22 (2H, m); 1.90(2H, t); 1.67 (2H, d); 1.33–1.16 (9H, m); 0.89 (3H, t).

Example 62 1-[3-(4-Butylpiperidin-1-yl)-propyl]-1H-indole-3-carbaldehyde(66) (35AKU-24)

To a solution of 1,3-dibromopropane (410 μl, 4.0 mmol) indimethylformamide (5 ml) was added a solution of1H-indole-3-carboxaldehyde (582 mg, 4.0 mmol) and KOH (456 mg, 8.1 mmol)in dimethylformanide (5 ml). After stirring for 24 h, 4-butylpiperidine(359 mg, 2.0 mmol) and additional KOH (200 mg, 3.6 mmol) were added.After stirring for 20 h, water and ethyl acetate were added. The phaseswere separated and the aqueous phase was re-extracted with ethyl acetate(3×15 ml). The combined organic phases were washed with brine, driedover MgSO4 and evaporated to dryness, giving 1.04 g of the crudeproduct. The crude product was purified by flash chromatography (0–10%methanol in DCM) yielding 252 mg (39%) of the title compound 66. TLC(10% methanol in DCM): R_(f)=0.5. HPLC-MS (Method A): M⁺=327.2(UV/MS(%)=99/96).

Example 63 {1-[3-(4-Butylpiperidin-1-yl)-propyl]-1H-indol-3-yl}-methanol(67) (35AKU-26)

To a solution of1-[3-(4-butylpiperidin-1-yl)-propyl]-1H-indole-3-carbaldehyde (120 mg,0.37 mmol) in methanol (2 ml) was slowly added a solution of NaBH₄ (9.2mg, 0.24 mmol) in 20 μl of 2M NaOH/1 ml of water. The mixture was thenstirred for 20 h at room temp. Additional NaBH₄ (12 mg, 0.32 mmol) wasadded and the mixture stirring for an additional 2 h. Another portion ofNaBH₄ (14 mg, 0.37 mmol) was added and the mixture was stirredovernight. Methanol was partly removed using a Rotavap, and ethylacetate (10 ml) and water (10 ml) were added. The phases were separatedand the aqueous phase was re-extracted with ethyl acetate (3×15 ml). Thecombined organic phases were dried over MgSO4 and evaporated to drynessgiving 93 mg (71%) of the title compound 67. TLC (10% methanol in DCM):R_(f)=0.4. HPLC-MS (Method A): M⁺=329.2 (UV/MS(%)-98/79). ¹H-NMR (400MHz, CDCl₃): δ=7.72 (1H, d); 7.36 (1H, d); 7.25–7.10 (3H, m); 4.86 (1H,s); 4.15 (2H, t); 2.84 (2H, d); 2.26 (2H, t); 1.99 (2H, m); 1.86 (2H,t); 1.71–1.62 (4H, m); 1.34–1.16 (9H, m); 0.90 (3H, t).

Example 641-[3-(4-Butylpiperidin-1-yl)-propyl]-2-phenyl-1H-benzoimidazole (68)(35AKU-28)

To a solution of 1,3-dibromopropane (205 μl, 2.0 mmol) indimethylformamide (5 ml) was added 2-phenylbenzimidazole (389 mg, 2.0mmol) and KOH (266 mg, 4.7 mmol). After stirring for 16 h at room temp.,4-butylpiperidine hydrochloride (176 mg, 1.0 mmol) was added. After 24 hstirring, additional KOH (270 mg, 4.8 mmol) was added and the mixtureheated at 90° C. for 3 h. After cooling, water (10 ml) and ethyl acetate(10 ml) were added. The phases were separated and the aqueous phase wasre-extracted with ethyl acetate (3×15 ml). The combined organic phaseswere washed with brine, dried over MgSO4 and concentrated in vacuo toproduce 643 mg of the crude material. The crude product was purified byflash chromatography (0–10% methanol in DCM) yielding 71 mg (19%) of thetitle compound 68. TLC (10% methanol in DCM): R_(f)=0.7. HPLC-MS (MethodA): M⁺=376.3 (UV/MS(%)=100/100). ¹H-NMR (400 MHz, CDCl₃): δ=7.85–7.27(9H, m); 4.32 (2H, t); 2.73 (2H, d); 2.25 (2H, t); 1.95 (2H, m); 1.81(2H, t); 1.62 (2H, d); 1.33–1.08 (9H, m); 0.90 (3H, t).

Example 65 1-[3-(4-Butylpiperidin-1-yl)-propyl]-3-chloro-1H-indazole(69) (35AKU-34)

To a solution of 1,3-dibromopropane (205 μl, 2.0 mmol) indimethylformamide (5 ml) was added 3-chloroindazole (306 mg, 2.0 mmol)and KOH (400 mg, 7.1 mmol). After stirring the suspension for 16 h,4-butylpiperidine hydrochloride (180 mg, 1.0 mmol) and dimethylformamide(2 ml) were added. After 20 h stirring, water (10 ml) and ethyl acetate(10 ml) were added. The phases were separated and the aqueous phase wasre-extracted with ethyl acetate (3×15 ml). The combined organic phaseswere washed with brine, dried over MgSO4 and concentrated in vacuo togive 500 mg of the crude product. The crude product was purified byflash chromatography (0–10% methanol in DCM) yielding 121 mg (36%) ofthe title compound 69. The oxalate-salt was prepared from oxalic acid(1.1 eq.) in diethyl ether. TLC (10% methanol in DCM): R_(f)=0.5.HPLC-MS (Method A): M⁺=334.1 (UV/MS(%)=100/100). ¹H-NMR (400 MHz,CDCl₃): δ 7.68–7.16 (4H, m); 4.43 (2H, t); 3.13 (2H, d); 2.62 (2H, t);2.35 (2H, m); 2.22 (2H, t); 1.76 (2H, d); 1.61–1.46 (2H, m); 1.36–1.24(7H, m); 0.89 (3H, t).

Example 66 1-[3-(4-Butylpiperidin-1-yl)-propyl]-6-nitro-1H-indazole (70)(35AKU40)

To a solution of 1,3-dibromopropane (205 μl, 2.0 mmol) indimethylformamide (20 ml) was added 6-nitroindazole (325 mg, 2.0 mmol)and K₂CO₃ (590 mg, 4.3 mmol). After stirring the suspension for 20 h,4-butylpiperidine hydrochloride (178 mg, 1.0 mmol) and dimethylformamide(5 ml) were added. After 20 h stirring, water (15 ml) and ethyl acetate(15 ml) were added. The phases were separated and the aqueous phase wasre-extracted with ethyl acetate (3×20 ml). The combined organic phaseswere washed with brine, dried over MgSO4 and concentrated in vacuo toproduce 511 mg of the crude product. The crude product was purified byion exchange chromatography (washout with 10% aq. NH₄OH (25%) inmethanol) and flash chromatography (0–10% methanol in DCM) yielding 21mg (6%) of the title compound 70. The oxalate-salt was prepared fromoxalic acid (1.1 eq.) in diethyl ether. TLC (10% methanol in DCM):R_(f)=0.4. HPLC-MS (Method A): M⁺=345.1 (UV/MS(%)=97/96). ¹H-NMR (400MHz, CDCl₃): δ=8.70 (1H, m); 8.07 (1H, m); 7.90 (1H, m); 7.75 (1H, m);4.56 (2H, t); 2.86 (2H, d); 2.32 (2H, t); 2.24 (2H, m); 1.92 (2H, t);1.68 (2H, m); 1.35–1.16 (9H, m); 0.89 (3H, t).

Example 67 Benzo[d]isoxazol-3-ol (35AKU-44) (71)

To a solution of salicylhydroxamic acid (1.53 g, 10 mmol) in THF (40 ml)was added a solution of carbonyldiimidazole (1.62 g, 20 mmol) intetrahydrofuran (20 ml). The mixture was stirred at reflux for 4 hrs.before evaporation to dryness. Water (20 ml) and conc. HCl (aq.) (5 ml)were added and the solution was refrigerated (5° C.) for 30 min. Theresulting precipitate was collected by filtration and washed with 2MHCl. The solid material was dissolved in methanol and concentrated invacuo yielding 725 mg (54%) of the title compound 71. TLC (10% methanolin DCM): R_(f)=0.2. HPLC-MS (Method A): M⁺=136.1 (UV/MS(%)=94/100).¹H-NMR (400 MHz, CDCl₃, MeOD): δ=7.73 (1H, m); 7.56 (1H, m); 7.38 (1H,m); 7.28 (1H, m); 3.87 (1H, s).

Example 68 3-(2-Chloroethoxy)-benzo[d]isoxazole (35AKU-45 (72))

To a solution of 1-bromo-2-chloroethane (250 μl, 3.0 mmol) indimethylformamide (10 ml) was added benzo[d]isoxazol-3-ol (400 mg, 3.0mmol) and K₂CO₃ (440 mg, 3.2 mmol). The mixture was stirred for 20 h andthen heated at 80° C. for 1 hr. Ethyl acetate (10 ml) and water (10 ml)were added. The phases were separated and the aqueous phase wasre-extracted with ethyl acetate (3×15 ml). The combined organic phaseswere washed with brine, dried over MgSO4 and concentrated in vacuo togive 543 mg of the crude product. The crude product was purified byflash chromatography (0–10% methanol in DCM) yielding 378 mg (64%) ofthe title compound 72. TLC (10% methanol in DCM): R_(f)=0.8. ¹H-NMR (400MHz, CDCl₃): δ=7.68 (1H, d); 7.55 (1H, t); 7.44 (1H, d); 7.28 (1H, t);4.72 (2H, t); 3.94 (2H, t).

Example 69 3-[2-(4-Butylpiperidin-1-yl)-ethoxy]-benzo[d]isoxazol (73)(35AKU-46)

A solution of 3-(2-chloroethoxy)-benzo[d]isoxazole (378 mg, 1.9 mmol),4-butylpiperidine hydrochloride (270 mg, 1.5 mmol) and K₂CO₃ (537 mg,3.9 mmol) dissolved in dimethylformamide (15 ml) was heated to 80° C.and stirred for 24 h. After cooling to room temp., water (15 ml) andethyl acetate (15 ml) were added. The phases were separated and theaqueous phase was re-extracted with ethyl acetate (3×20 ml). Thecombined organic phases were washed with brine, dried over MgSO4 andconcentrated in vacuo to give 586 mg of the crude material. The crudeproduct was purified by flash chromatography (0–5% methanol in DCM)yielding 157 mg (35%) of the title compound 73. The oxalate-salt wasprepared from oxalic acid (1.1 eq.) in diethyl ether. TLC (5% methanolin DCM): R_(f)=0.3. HPLC-MS (Method A): M⁺=303.1 (UV/MS(%)=100/100).¹H-NMR (400 MHz, CDCl₃): δ=7.69–7.22 (4H, m); 4.57 (2H, t); 2.99 (2H,d); 2.88 (2H, t); 2.11 (2H, t); 1.68 (2H, m); 1.32–1.18 (9H, m); 0.89(3H, t).

Example 70 3-(1H-Indol-3-yl)-propan-1-ol (74) (32HS28)

A suspension of lithiumaluminium hydride (4.68 g, 126 mmol) in anhydrousdiethyl ether (230 ml) was stirred heavily. 3-Indolepropionic acid (10.0g, 53 mmol) was dissolved in anhydrous diethyl ether and added drop wisewhile the reaction was at reflux. The reaction mixture was furtherrefluxed for 2 h and then stirred at room temperature (rt) overnight.Water (25 ml) was added slowly, followed by an aqueous solution of H₂SO₄(1:3 H₂O/conc. H₂SO₄) (20 ml). The resulting clear mixture was extractedwith diethyl ether (3×110 ml), and the combined organic phases werewashed with brine, dried (Na₂SO₄) filtered and concentrated in vacuo togive a crude oil of the title compound (74) (1.8 g). The crude materialwas used without further purification.

Example 71 3-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indole hydrochloride(75) (32HS34)

The crude 3-(1H-indol-3-yl)-propan-1-ol (1.8 g) was dissolved inanhydrous THF and cooled to −40° C. Triethylamine (720 mg, 7.1 mmol) wasadded by syringe, followed by methanesulfonyl chloride (750 mg, 6.5mmol). The mixture was allowed to warm to 20° C., and then filtered andconcentrated in vacuo to yield a crude product that was redissolved inDCM and washed with water. The organic phase was dried over MgSO4,filtered and concentrated in vacuo to a brown oil. This material wasused immediately without further purification.

4-n-Butylpiperidine hydrochloride (967 mg, 5.4 mmol) and Na₂CO₃ (1.28 g,12 mmol) were suspended in DME, stirred at rt for 30 min, and then addedto the crude material in DME. The resulting mixture was stirred at 82°C. overnight. The mixture was cooled prior to addition of ethyl acetate(15 ml) and water (15 ml), extracted with ethyl acetate (3×20 ml). Thecombined organic phases were washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. Purification by preparative HPLC followed bytreatment with HCl in dioxane (4M, 2 ml) produced the title compound(75) as white crystals after washing with DCM. Yield: 130 mg, 0.3%(overall). HPLC-MS (Method A): M⁺=298.3 (UV/MS(%)=100/100). ¹H-NMR (400MHz, CD₃OD): δ 7.55 (d, 1H), 7.34 (d, 1H), 7.09 (m, 2H), 7.01 (t, 1H9),3.46 (m, 2H), 3.09 (m, 2H), 2.87 (m, 5H), 2.14 (m, 2H) 1.91 (2, 2H),1.58–1.24 (m, 9H), 0.90 (t, 3H).

Example 72 4-(4-Butylpiperidine-1-yl)-butyric acid methyl ester (76)(40-LH-58)

To a solution of 4-bromo-butyric acid methyl ester (1.35 g, 7.5 mmol) indry acetonitrile (10 ml) was added 4-butylpiperidine (1.00 g, 7.1 mmol)and K₂CO₃ (1.10 g, 7.8 mmol). After stirring at rt for 12 h, thereaction mixture was evaporated to dryness followed by addition of water(15 ml). The aqueous phase was extracted with ethyl acetate (3×20 ml)and the combined organic phases were dried (Na₂SO₄) and concentrated invacuo to produce 1.71 g of the crude title compound 76. The crudeproduct was purified by flash chromatography (MeOH:ethyl acetate; 2:8)to give the pure title compound. Yield 1.27 g (74%). ¹H NMR (CD₃OD): δ3.65 (s, 3H), 2.93 (d, 2H), 2.33 (q, 4H), 1.98 (t, 2H), 1.81 (qv, 2H),1.69 (d, 2H), 1.35–1.18 (m, 9H), 0.90 (t, 3H).

Example 732-[3-(4-Butylpiperidin-1-yl)-propyl]-1-methyl-1H-benzimidazole (77)(40-LH-59B)

A mixture of N-methyl-benzene-1,2-diamine (68 mg, 0.56 mmol) and4-(4-Butylpiperidine-1-yl)-butyric acid methyl ester (130 mg, 0.54 mmol)in polyphosphoric acid (1 ml) was heated and shaken in a sealed vial at150° C. for 1.5 h. The reaction mixture was poured into an ice-cold bath(NaOH (4N): ice 1:1) with stirring, upon which a grey precipitateformed. The grey solid was filtered and washed with cold ether. Theoxalate-salt was prepared from oxalic acid (1.1 eq.) in diethyl ether.Yield 141 mg (92%). ¹H NMR (CDCl₃): δ 7.71 (m, 1H), 7.30–7.19 (m, 3H),3.74 (s, 3H), 2.90 (q, 4H), 2.43 (t, 2H), 2.06 (qv, 2H), 1.89 (t, 2H),1.65 (d, 2H), 1.31–1.14 (m, 9H), 0.89 (t, 3H).

Example 74 1H-Indazole-3-carboxylic acid(2-(4-butylpiperidin)-1-yl-ethyl)-amide (78)(40-LH-70-17B)

To a shaken solution of 1H-indazole-3-carboxylic acid (49 mg, 0.30 mmol)and N-hydroxysuccinimide (36 mg, 0.31 mmol) in dry DMF (2 ml) was addeda solution of dicyclohexylcarbodiimide (62 mg, 0.30 mmol) in dry DMF (1ml). The mixture was shaken for 16 h followed by addition of2-(4-butylpiperidin-1-yl)-ethylamine (28 mg, 0.15 mmol). The reactionmixture was further shaken for another 24 h followed by filtration. Theorganic phase was loaded onto a Varian SCX ion exchange column. Thecolumn was washed sequentially with methanol (5 ml), isopropanol (5 ml),and methanol (5 ml). The product was eluted from the column using 5%ammonium in methanol (5 ml). The solute was concentrated in vacuo,dissolved in acetone, dried (K₂CO₃) and concentrated in vacuo to producethe title compound 78. Yield 47 mg (95%). ¹H NMR (CD₃OD): δ 8.21 (d,1H), 7.56 (d, 1H), 7.40 (dt, 1H), 7.24 (dt, 1H), 3.59 (t, 2H), 3.01 (bd,2H), 2.63 (t, 2H), 2.08 (t, 2H), 1.71 (d, 2H), 1.34–1.21 (m, 9H), 0.90(t, 3H).

Example 75 1-[3-(4-Butylpiperidin-1-yl)-propyl]-5-nitro-1H-indazole (79)(64LHY29-1); and Example 76.2-[3-(4-butylpiperidin-1-yl)-propyl]-5-nitro-2H-indazole (80)(64LHY29-2)

To a cooled solution (−78° C.) of 5-nitroindazole (41.20 mg, 0.25 mmol)in THF (1 ml) was added a solution of n-buthyllithium in hexane (1.5 M,0.17 ml, 0.25 mmol) followed by addition of 1-bromo-3-iodopropane (27μl, 0.25 mmol). After 16 h at rt the mixture was concentrated in vacuo.Methyl ethylketone (1 ml) and 4-butylpiperidine (35.3 mg, 0.25 mmol)were added. The reaction mixture was shaken for 16 h at 60° C. followedby filtration, and the organic layer was then evaporated to dryness. Thesolid was dissolved in methanol (1 ml) prior to loading onto a VarianSCX ion exchange resin column. The column was washed with methanol (3×6ml) and the product eluted with 10% NH₃ in methanol (5 ml). The solutewas concentrated in vacuo. The two isomers were formed at a 1:1 ratioaccording to LC-MS analysis of the crude mixture. The two isomers wereisolated after purification by preparative HPLC. 79 (64LHY29-1): ¹H-NMR(CDCl₃): δ 0.88 (t, 3H), 1.18–1.33 (m, 9H), 1.73–1.64 (bd. d, 2H), 1.92(bd. t, 2H), 2.21 (ddd, 2H), 2.30 (dd, 2H), 2.85 (bd. d, 2H), 4.55 (t,2H), 7.75 (ddd, 1H), 8.10 (dd, 1H), 8.24 (d, 1H), 8.73 (dd, 1H); ¹³C-NMR(CDCl₃): δ 14.0, 22.8, 27.3, 28.9 (2C), 32.3, 35.6, 36.1, 52.1, 53.9(2C), 54.7, 118.2, 119.2, 119.9, 120.1, 127.3, 143.0, 149.8; LC-MS:(M+H)⁺ 445.2, t_(r) 3.69 min. 80 (64LHY29-2): ¹H-NMR (CDCl₃): δ 0.90(t,3H), 1.14–1.38 (m, 9H), 1.62 (bd. d, 2H), 1.86 (bd. dd, 2H), 2.16(ddd, 2H), 2.21 (dd, 2H), 2.75 (bd d, 2H), 4.50 (t, 2H), 7.59 (ddd, 1H),8.21 (d, 1H), 8.25 (dd, 1H), 8.73 (dd, 1H); ¹³C-NMR (CDCl₃): δ 14.3,23.1, 27.3, 29.2, 32.8 (2C), 36.0, 36.5, 47.2, 54.2 (2C), 55.2, 110.0,119.1, 121.3, 123.0, 136.0, 141.8, 142.5; LC-MS: (M+H)⁺ 445.2, t_(r)5.30 min.

General Procedure for the Preparation of Indole Derivatives.

Indole (1.20 mmol) was taken up in dry DMF (3 ml) prior to addition ofsodium hydride (2.50 mmol) at rt., followed by addition of3-chloro-1-iodo-propane (0.20 g, 1.0 mmol). The reaction mixture wasshaken in a sealed vial at rt. for 16 h. 4-Butyl-piperidine (130 mg, 0.9mmol) was added and the reaction mixture was further shaken at 50° C.for 72 h. The mixture was filtered and the filtrate was loaded onto aVarian SCX ion exchange column. The column was washed with methanol (10ml, 2 column volumes) and the product was eluted from the column using5% ammonium hydroxide in methanol (5 ml, 1 column volumes). The solutewas concentrated in vacuo to produce the title compounds (79, 80).

Example 77 1-[3-(4-Butyl-piperidin-1-yl)-propyl]-2-methyl-1H-indole (81)(55-LH-1-1-(1402))

The reaction was carried out according to the general procedure using2-methyl-1H-indole (157 mg, 1.20 mmol). The crude product was furtherpurified by flash chromatography (MeOH: ethyl acetate; 1:4) to give thetitle compound 81. Yield 19 mg (21%). (UV/MS(%)=98/89); ¹H NMR (CDCl₃):δ 7.50 (d, 1H), 7.31 (d, 1H), 7.12 (dt, 1H), 7.04 (dt, 1H), 6.23 (s,1H), 4.12 (t, 2H), 2.87 (d, 2H), 2.44 (s, 3H), 2.31 (t, 2H), 1.98–1.83(m, 4H), 1.67 (d, 2H), 1.32–1.19 (m, 9H), 0.89 (t, 3H).

Example 781-{1-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indol-3-yl}-ethanone (82)(55-LH-1-2-(1403)

The reaction was carried out according to the general procedure using1-(1H-indol-3-yl)-ethanone (191 mg, 1.20 mmol) to give the titlecompound 82. Yield 33 mg (32%). (UV/MS(%)=99/91); ¹H NMR (CDCl₃): δ8.39–8.34 (m, 1H), 7.80 (s, 1H), 7.41–7.36 (m, 1H), 7.30–7.25 (m, 2H),4.24 (t, 2H), 2.80 (d, 2H), 2.21 (t, 2H), 2.01 (qv, 2H), 1.86 (t, 2H),1.69 (d, 2H), 1.32–1.19 (m, 9H), 0.89 (t, 3H).

Example 79{1-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indol-3-yl}-acetonitrile (83)(55-LH-1-3-(1404)

The reaction was carried out according to the general procedure using(1H-indol-3-yl)-acetonitrile (187 mg, 1.20 mmol) to give the titlecompound 83. Yield 33 mg (11%). (UV/MS(%)=99192); ¹H NMR (CDCl₃): δ 7.55(d, 1H), 7.38 (d, 1H), 7.24 (t, 1H), 7.15 (t, 1H), 4.17 (t, 2H), 3.82(s, 2H), 2.82 (d, 2H), 2.23 (t, 2H), 1.98 (qv, 2H), 1.85 (t, 2H), 1.67(d, 2H), 1.33–1.17 (m, 9H), 0.89 (t, 3H).

Example 801-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indole-3-carbonitrile (84)(55-LH-1-4-(1405))

The reaction was carried out according to the general procedure using1H-indole-3-carbonitrile (170 mg, 1.20 mmol) to give the title compound84. Yield 30 mg (31%). (UV/MS(%)=99/96); ¹H NMR (CDCl₃): δ 7.75 (d, 1H),7.63 (s, 1H), 7.45 (d, 1H), 7.35–7.25 (m, 2H), 4.25 (t, 2H), 2.79 (d,2H), 2.20 (t, 2H), 1.99 (qv, 2H), 1.86 (t, 2H), 1.68 (d, 2H), 1.33–1.18(m, 9H), 0.89 (t, 3H).

General Procedure for the Preparation of Benzimidazole Derivatives.

Benzimidazole (0.60 mmol) was taken up in dry THF (1 ml) prior todrop-wise addition of n-BuLi (1.6 M in Hexane) (413 μl, 0.66 mmol) atrt. The mixture was stirred for 15 min. followed by addition of1,3-dibromo-propane (100 mg, 0.50 mmol) and then left at rt. for 16 h.4-Butyl-piperidine (64 mg, 0.45 mmol) was added and the reaction mixturewas shaken at 60° C. for 72 h. The mixture was filtered and the filtrateconcentrated in vacuo prior to purification by preparative HPLC.

Example 811-[3-(4-Butyl-piperidin-1-yl)-propyl]-5,6-dimethyl-1H-benzoimidazole(85) (55-LH-8-2 (1387))

The reaction was carried out according to the general procedure using5,6-dimethyl-benzoimidazole (88 mg, 0.60 mmol) to give the titlecompound 85. Yield 20 mg (14%). (MS(%)=100); ¹H NMR (CDCl₃): δ 7.78 (s,1H), 7.55 (s, 1H), 7.18 (d, 1H), 4.20 (t, 2H), 2.81 (d, 2H), 2.39 (s,3H), 2.37 (s, 3H), 2.22 (t, 2H), 2.00 (qv, 2H), 1.85 (t, 2H), 1.68 (d,2H), 1.33–1.18 (m, 9H), 0.90 (t, 3H).

Example 821-[3-(4-Butyl-piperidin-1-yl)-propyl]-5(6)-dimethyl-1H-benzoimidazole(86) (55-LH-8-3 (1388))

The reaction was carried out according to the general procedure using5-methyl-benzoimidazole (79 mg, 0.60 mmol) to give the title compound(86) as a 50/50 mixture of the two regio isomers, according to ¹H-NMR.Yield 42 mg (30%). (UV/MS(%)=100/100).

Example 831-[3-(4-Butyl-piperidin-1-yl)-propyl]-5-methoxy-1H-benzoimidazole (87)(55-LH-8-6 (1393))

The reaction was carried out according to the general procedure using5-methoxy-benzoimidazole (89 mg, 0.60 mmol) to give the title compound(87) as a 50/50 mixture of the two regio isomers, according to ¹H-NMR.Yield 62 mg (42%). (UV/MS(%)=100/100).

Example 84{1-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-benzoimidazol-2-yl}-methanol(88) (55-LH-8-9 (1400))

The reaction was carried out according to the general procedure using(1H-benzoimidazol-2-yl)-methanol (89 mg, 0.60 mmol) to give the titlecompound 88. Yield 56 mg (38%). (UV/MS(%)=95/85); ¹H NMR (CDCl₃): δ7.69–7.65 (m, 1H), 7.32–7.28 (m, 1H), 7.21–7.18 (m, 2H), 4.88 (s, 2H),4.38 (t, 2H), 2.70 (d, 2H), 2.18–2.06 (m, 4H), 1.74 (t, 2H), 1.58 (d,2H), 1.24–1.14 (m, 9H), 0.81 (t, 3H).

Example 851-[3-(4-Butyl-piperidin-1-yl)-propyl]-2-trifuoromethyl-1H-benzoimidazole(89) (55-LH-8-10 (1401))

The reaction was carried out according to the general procedure using2-trifuoromethyl-1H-benzoimidazole (112 mg, 0.60 mmol) to give the titlecompound 89. Yield 48 mg (29%). (UV/MS(%)=100/95); ¹H NMR (CDCl₃): δ7.78 (d, 1H), 7.74 (d, 1H), 7.49 (t, 1H), 7.41 (t, 1H), 4.48 (t, 2H),2.86 (d, 2H), 2.41 (t, 2H), 2.08 (qv, 2H), 1.92 (t, 2H), 1.67 (d, 2H),1.31–1.15 (m, 9H), 0.89 (t, 3H).

Example 86 (2-Trimethylstannanyl-phenyl)-carbamic acid tert-butyl ester(90) (53MF36)

To a solution of phenyl-carbamic acid tert-butyl ester (10.02 g, 52mmol) in dry DMF (150 ml) was dropwise added tert-Buli (1.7 M in hexane)(80 ml, 0.14 mol) at −70° C. The reaction mixture was stirred for 30 minat −70° C. and 2 h at −20° C. before adding a solution oftrimethyltinchloride in dry THF (1 M) (77.0 ml, 78 mmol). The reactionmixture was further stirred at −20° C. for 1 h followed by addition ofan aqueous ammonium chloride solution (15%) (100 ml). The mixture wasextracted with diethyl ether (3×300 ml) and the combined organic phaseswere dried over MgSO4 and evaporated in vacuo to give the crude titlecompound (90) (17.0 g), which was used in the next reaction withoutfurther purification.

Example 87 [2-(4-Chloro-butyryl)-phenyl]-carbamic acid tert-butyl ester(91) (53MF37)

To a mixture of (2-trimethylstannanyl-phenyl)-carbamic acid tert-butylester (17.0 g, 36 mmol) in dry toluene (300 ml) was added4-chloro-butyryl chloride (5.3 g, 38 mmol) anddichlorobis(acetonitrile)palladium (II) (300 mg, 1.2 mmol). The reactionmixture was heated to reflux and left for 12 h., followed by evaporationto dryness and column chromatography (heptane:ethyl acetate; 10:1) toproduce the title compound 91. Yield 7.2 g (47% from the phenyl-carbamicacid tert-butyl ester).

Example 88 {2-[4-(4-Butyl-piperidine-1-yl)-butyryl]-phenyl}-carbamicacid tert-butyl ester (92) (53MF38)

A flash was charged with [2-(4-chloro-butyryl)-phenyl]-carbamic acidtert-butyl ester (2.1 g, 7.1 mmol) and 4-butyl-piperidine (1.2 g, 8.5mmol) before addition of pyridine (5 ml). To the reaction mixture wasadded potassium carbonate (1.17 g, 8.5 mmol) and the mixture was stirredat 100° C. for 12 h. Water (50 ml) was added followed by extraction withethyl acetate (3×150 ml). The combined organic phases were dried overMgSO4, filtered and evaporated to dryness. The crude material wassubjected to column chromatography (DCM:methanol; 20:1) which producedthe pure title compound (92) (1.48 g, 52%).

Example 89 3-[3-(4-Butyl-piperidine-1-yl)-propyl]-1H-indazole, HCl (93)(53MF39)

A solution of {2-[4-(4-butyl-piperidine-1-yl)-butyryl]-phenyl}-carbamicacid tert-butyl ester (1.48 g, 3.7 mmol) in a solution of HCl in dioxane(4 N) (20 ml) was stirred at rt for 1 h before evaporation to dryness.The residue was dissolved in HCl (conc.) (15 ml) prior to addition of asolution of sodium nitrite (255 mg, 3.7 mmol) dissolved in water (3 ml).The mixture was stirred at 0° C. for 1 h before addition of stannylchloride (1.7 g, 7.4 mmol) and then further stirred at rt for 3 h. ThepH of the reaction mixture was adjusted with NaOH (2 N) until basic,followed by extraction with ethyl acetate (3×400 ml). The combinedorganic phases were dried over MgSO4, filtered and evaporated in vacuo.The crude material was subjected to column chromatography (DCM:methanol;20:1), which produced the crude title compound 93. The crude compoundwas dissolved in diethyl ether followed by addition of HCl in ether (1.0M) and stirred for 0.5 h. The solution was evaporated to dryness and thesolid material was recrystallised twice from DCM:diethyl ether toproduce the pure title compound. Yield 0.44 g (32%). (UV/MS(%)=100/100);mp: 160.5–164.0° C.; ¹H NMR (CD₃OD): δ 7.96 (d, 1H), 7.62 (d, 2H), 7.33(d, 1H), 3.58 (dt, 2H), 3.24–3.19 (m, 4H), 2.95 (t, 2H), 2.33 (qv, 2H),1.97 (d, 2H), 1.65–1.28 (m, 9H), 0.91 (t, 3H). ¹³C NMR (CD₃OD): 143.9,141.0, 130.3, 122.5, 120.8, 120.5, 110.9, 56.4, 53.2, 35.4, 33.6, 29.7,28.5, 23.1, 22.7, 22.6, 13.1.

Example 90 3-[3-(4-Butyl-piperidine-1-yl)-propyl]-5-nitro-1H-indazole(94) (39MF43NO2); and Example 913-[3-(4-Butyl-piperidine-1-yl)-propyl]-5,7-dinitro-1H-indazole (95)(39MF43DiNO₂)

A solution of 3-[3-(4-butyl-piperidine-1-yl)-propyl]-1H-indazole (120mg, 0.4 mmol) in a 1:1 mixture of nitric acid (fuming) and sulfuric acid(conc.) (2 ml) was stirred at 0° C. for 1.5 h. The pH of the mixture wasadjusted with NaOH (8 N) whereupon a yellow oily material precipitated.The material was filtered and subjected to preparative TLC(DCM:methanol; 10:1) which produced the two pure title compounds. Yield:25 mg (18%) (3-[3-(4-Butyl-piperidine-1-yl)-propyl]-5-nitro-1H-indazole)(94). ¹H NMR (CDCl₃): δ 8.45 (s, 1H), 8.01 (d, 2H), 7.48 (d, 1H), 3.48(d, 2H), 3.18–2.95 (m, 4H), 2.62 (t, 2H), 2.27 (qv, 2H), 1.82 (d, 2H),1.58 (qv, 2H), 1.44–1.38 (m, 1H), 1.30–1.19 (m, 6H), 0.91 (t, 3H). ¹³CNMR(CDCl₃): 147.4, 143.4, 141.9, 121.6, 121.1, 117.7, 111.3, 57.4, 53.6,35.4, 34.4, 30.0, 28.9, 24.2, 23.5, 22.9, 14.2. Yield: 10 mg (6%)(3-[3-(4-Butyl-piperidine-1-yl)-propyl]-5,7-dinitro-1H-indazole) (95).¹H NMR (CDCl₃): δ 9.18 (d, 1H), 9.05 (d, 1H), 3.18–3.10 (m, 4H), 2.68(t, 2H), 2.25–2.14 (m, 4H), 1.74 (d, 2H), 1.45–1.22 (m, 7H), 0.91 (t,3H).

Example 924-(4-Butyl-piperidin-1-yl)-1-(2-metylsulfanyl-phenyl)-butan-1-one (96)(65MF07)

To a stirred solution of 2-bromothioanisole (12.85 g, 63.3 mmol) in dryTHF (60 ml) at −78° C. was added n-BuLi (1.6 N in hexane) (41 ml, 65.3mmol) via a syringe over 30 min. The reaction mixture was furtherstirred at −78° C. for 30 min. prior to the addition of a solution of4-(4-butyl-cyclohexyl)-N-methoxy-N-methyl-butyramide (11.41 g, 42.2mmol) dissolved in dry THF (10 ml). The mixture was held at −78° C. for0.5 h and at rt for 0.5 h before addition of water (100 ml) and byextraction with ethyl acetate (3×150 ml). The combined organic phaseswere dried over MgSO4, filtered and evaporated in vacuo to produce thecrude title compound 96 (11.9 g). Purity according LC-MS analysis:(UV/MS(%)=90/91).

Example 93 3-[3-(4-Butyl-piperidin-1-yl)-propyl]-benzo[d]isothiazole(97) (65MF08)

A mixture of crude4-(4-butyl-piperidin-1-yl)-1-(2-metylsulfanyl-phenyl)-butan-1-one (11.9g, 36 mmol) and hydroxylamine-O-sulfonic acid (6.11 g, 54 mmol) inacetic acid (500 ml) was stirred at rt for 72 h followed by heating at100° C. for 24 h. The reaction mixture was cooled to rt and the pHadjusted with 2 N NaOH to a basic condition (pH=9), before extractionwith ethyl acetate (3×400 ml). The combined organic phases were driedover MgSO4, filtered and evaporated in vacuo to produce 12.1 g of thecrude product. The crude product was purified by column chromatography(DCM:MeOH; 20:1) to yield the title compound 97. Yield 3.67 g (18.3%)from 2-bromothioanisole. The oxalate salt was formed by addition ofoxalic acid and recrystallised from methanol-diethyl ether to give whitecrystals, which were filtered and dried. (UV/MS(%)=90/91),mp=193.4–194.0° C. ¹H NMR (CDCl₃): δ 7.98 (d, 1H), 7.91 (d, 1H), 7.50(t, 1H), 7.41 (t, 1H), 3.14 (t, 2H), 2.92 (d, 2H), 2.46 (t, 2H), 2.18(qv, 2H), 1.92 (t, 2H), 1.66 (d, 2H), 1.35–1.18 (m, 9H), 0.88 (t, 3H).¹³C NMR (CDCl₃): 166.6, 152.5, 134.9, 127.6, 124.5, 123.6, 120.0, 58.5,54.2, 36.4, 35.9, 32.5, 29.7, 25.5, 23.1, 14.2.

Example 94 3-[3-(4-Butyl-piperidin-1-yl)-propyl]-5-methoxy-1H-indazole(98) (53MF35)

A small flask was charged with1-(2-amino-5-methoxy-phenyl)-4-(4-butyl-piperidin-1-yl)-butan-1-one(1.58 g, 47 mmol) in conc. HCl (15 ml). The mixture was cooled to 0° C.followed by addition of sodium nitrite (0.61 g, 88 mmol) and water (3ml) and stirring at 0° C. for 2 h. Addition of tin(II) chloridedihydrate (2.68 g, 11.9 mmol) produced a precipitated that was filtered,washed twice with ice-cold water and dried. The filtrate was dissolvedin ethyl acetate (100 ml) and 1N NaOH (150 ml), followed by extractionwith ethyl acetate (3×150 ml). The combined organic phases were driedover MgSO4, filtered and evaporated in vacuo to produce 1.30 g of thecrude product. The crude product was purified by column chromatography(DCM:MeOH; 20:1) to yield the title compound 98. The oxalate salt wasformed by addition of oxalic acid and recrystallised frommethanol-diethyl ether to give white crystals that were filtered anddried. Yield 0.97 g (49%). ¹H NMR (CDCl₃): δ 7.32 (dd, 1H), 7.03 (dd,1H), 6.98 (d, 1H), 3.85 (s, 3H), 3.10 (d, 2H), 2.96 (t, 2H), 2.61 (t,2H), 2.15–2.05 (m, 4H), 1.68 (d, 2H), 1.40–1.20 (m, 9H), 0.87 (t, 3H).¹³C NMR(CDCl₃): 177.2, 154.5, 145.6, 137.4, 122.4, 119.0, 111.2, 99.6,58.0, 55.9, 53.5, 36.1, 35.5, 31.5, 29.1, 25.2, 24.9, 23.4, 23.0, 14.2.

Example 95 3-[3-(4-Butyl-piperidin-1-yl)-propyl]-4-methoxy-1H-indazole(99) (53MF470)

To a solution of 3-(3-chloro-propyl)-4-methoxy-1H-indazole (0.99 g, 4.41mmol) in acetonitrile (25 ml) was added 4-butylpiperidine (0.61 g, 4.41mmol) at rt. The reaction mixture was stirred at rt. for 3 days beforeaddition of water (50 ml). The aqueous phase was extracted with ethylacetate (3×50 ml) and the combined organic phases were dried over MgSO4,filtered and evaporated in vacuo to produce 1.40 g of the crude product.The crude product was purified by column chromatography (ethylacetate:MeOH:Et₃N; 10:5:3) to yield the title compound 99. Yield 0.65 g(45%). ¹H NMR (CDCl₃): δ 7.24 (d, 1H), 7.00 (d, 1H), 6.41 (t, 1H), 3.91(s, 3H), 3.58 (d, 2H), 3.20–2.99 (m, 4H), 2.55 (t, 2H), 2.22 (qv, 2H),1.81 (d, 2H), 1.61 (q, 2H), 1.41–1.08 (m, 7H), 0.87 (t, 3H). ¹³C NMR(CDCl₃): 154.9, 144.3, 143.3, 129.2, 113.1, 103.1, 99.8, 57.1, 55.4,53.3, 35.3, 34.3, 29.5, 28.8, 25.6, 23.1, 22.8, 14.1.

Example 96 3-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methoxy-1H-indazole(100) (53MF47P)

To a solution of 3-(3-chloro-propyl)-6-methoxy-1H-indazole (0.99 g, 4.41mmol) in acetonitrile (25 ml) was added 4-butylpiperidine (0.61 g, 4.41mmol) at rt. The reaction mixture was stirred at rt. for 3 days beforeaddition of water (50 ml). The aqueous phase was extracted with ethylacetate (3×50 ml) and the combined organic phases were dried over MgSO4,filtered and evaporated in vacuo to produce 0.85 g of the crude product.The crude product was purified by column chromatography (ethylacetate:MeOH:Et₃N; 10:5:3) to yield the title compound 100. Yield 0.55 g(38%). ¹H NMR (CDCl₃): δ 7.42 (d, 1H), 6.80–6.72 (3, 2H), 3.80 (s, 3H),3.60 (d, 2H), 3.11–2.92 (m, 4H), 2.55 (t, 2H), 2.23 (qv, 2H), 1.79 (d,2H), 1.58 (q, 2H), 1.40–1.08 (m, 7H), 0.83 (t, 3H). ¹³C NMR (CDCl₃):160.8, 143.8, 142.6, 120.7, 116.2, 114.0, 91.2, 57.1, 55.6, 53.4, 35.3,34.3, 29.5, 28.8, 23.7, 22.8, 22.7, 14.1.

Example 97 3-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indazole-4-ol(101)(53MF51)

3-[3-(4-Butyl-piperidin-1-yl)-propyl]-4-methoxy-1H-indazole (28 mg, 0.09mmol) was dissolved in dry DCM (1.0 ml) and cooled to 0° C. beforeaddition of 1M bromotribromide solution in DCM (0.50 ml, 0.50 mmol). Themixture was left at rt for 12 h, followed by addition of water (5 ml)and 2N NaOH (10 ml). The aqueous phase was extracted with DCM (3×25 ml)and the combined organic phases were dried over MgSO4, filtered andevaporated in vacuo to produce 13 mg of the crude product. Purificationby preparative HPLC followed by treatment with HCl in dioxane (4M, 2 ml)yielded the title compound (101) as white crystals after washing withDCM. Yield: 6.0 mg, 17% ¹H NMR (CDCl₃): δ 7.18 (t, 1H), 6.81 (d, 1H),6.50 (t, 1H), 2.85 (d, 2H), 2.23 (t, 2H), 1.98 (qv, 2H), 1.83 (t, 2H),1.62 (d, 2H), 1.41 (d, 2H), 1.21–1.01 (m, 9H), 0.78 (t, 3H).

Example 98 3-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indazole-6-ol (102)(53MF52)

3-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methoxy-1H-indazole (28 mg, 0.09mmol) was dissolved in dry DCM (1.0 ml) and cooled to 0° C. beforeaddition of 1M bromotribromide solution in DCM (0.50 ml, 0.50 mmol). Themixture was held at rt for 12 h, followed by addition of water (5 ml)and 2N NaOH (10 ml). The aqueous phase was extracted with DCM (3×25 ml)and the combined organic phases were dried over MgSO4, filtered andevaporated in vacuo to produce 17 mg of the crude product. Purificationby preparative HPLC followed by treatment with HCl in dioxane (4M, 2 ml)yielded the title compound (102) as white crystals after washing withDCM. Yield: 10 mg, 17%. ¹H NMR (CD₃OD): δ 7.54 (d, 1H), 6.77 (s, 1H),6.71 (d, 1H), 3.55 (d, 2H), 3.15 (t, 2H), 3.04 (t, 2H), 2.90 (dt, 2H),2.22 (qv, 2H), 1.97 (d, 2H), 1.58–1.28 (m, 9H), 0.92 (t, 3H). ¹³C NMR(CD₃OD): 159.0, 145.5, 144.4, 121.7, 117.2, 113.7, 94.4, 58.2, 54.3,36.5, 34.8, 31.0, 29.7, 24.7, 24.3, 23.7, 14.3.

Example 99 3-[3-(4-Butyl-piperidin-1-yl)-propyl]-1H-indazole-5-ol (103)(53MF50)

3-[3-(4-Butyl-piperidin-1-yl)-propyl]-5-methoxy-1H-indazole (28 mg, 0.09mmol) was dissolved in dry DCM (1.0 ml) and cooled to 0° C. beforeaddition of 1M bromotribromide solution in DCM (0.50 ml, 0.50 mmol). Themixture was held at rt for 12 h, followed by addition of water (5 ml)and 2N NaOH (10 ml). The aqueous phase was extracted with DCM (3×25 ml)and the combined organic phases were dried over MgSO4, filtered andevaporated in vacuo to produce 14 mg of the crude product. Purificationby preparative HPLC followed by treatment with HCl in dioxane (4M, 2 ml)yielded the title compound (103) as white crystals after washing withDCM. Yield: 16 mg, 60%. ¹H NMR (CD₃OD): δ 7.54 (d, 1H), 6.77 (s, 1H),6.71 (d, 1H), 3.55 (d, 2H), 3.15 (t, 2H), 3.04 (t, 2H), 2.90 (dt, 2H),2.22 (qv, 2H), 1.97 (d, 2H), 1.58–1.28 (m, 9H), 0.92 (t, 3H). ¹³C NMR(CD₃OD): 159.0, 145.5, 144.4, 121.7, 117.2, 113.7, 94.4, 58.2, 54.3,36.5, 34.8, 31.0, 29.7, 24.7, 24.3, 23.7, 14.3.

Example 100 Screening Of Test Compounds In An Assay Using MuscarinicReceptor Subtypes m1, m2, m3, m4 and m5.

The m1, m2, m3, m4 and m5 muscarinic receptor subtypes were clonedsubstantially as described by Bonner et al., Science 273:527(1987) andBonner et al., Neuron 1:403 (1988). R-SAT assays were carried outsubstantially as described in U.S. Pat. Nos. 5,707,798, 5,912,132, and5,955,281, and by Braüner-Osborne & Brann, Eur. J. Pharmacol. 295:93(1995). NIH-3T3 cells (available from the American Type CultureCollection as ATCC CRL 1658) were transfected with plasmid DNA encodingthe m1, m2, m3, m4 or m5 receptors and plasmid DNA encodingβ-galactosidase. Transfected cells were grown in the presence of between1 nM and 40 μM of the test compound for 5 days. On day 5, the cells werelysed using 0.5% Nonidet-P and β-galactosidase expression was quantifiedusing the chromogenic substrate o-nitrophenyl-β-D-galactoside (ONGP).

Data were normalized relative to the maximum response of the cells tothe muscarinic agonist carbachol, and the following equation was fittedto the data:response=minimum+(maximum−minimum)/(1+(EC50/[ligand]))

-   -   Where [ligand]=ligand concentration.    -   % Efficacy was defined as:        (maximum−minimum)/(maximum response of cells to carbachol).    -   pEC50=−log (EC50).

Where data gave a bell-shaped curve, “maximum” was defined as thehighest observed response.

The results, which demonstrate the selective agonist activity of severalcompounds of the invention, are below presented in Table 1.

TABLE 1 Selectivity of Muscarinic Agonists m1 m2 m3 m4 m5 Example % EffpEC50 % Eff pEC50 % Eff pEC50 % Eff pEC50 % Eff pEC50 12 59 5.9 noresponse no response no response 19 86 7.3 no response no response 706.5 no response 24 75 6.9 no response no response 41 6.3 no response 2838 6.5 no response no response no response 32 52 6.4 no response noresponse no response no response 41 81 6.9 no response no response 696.2 31 <5.5 42 51 7.1 43 66 6.3 30 6.0 no response 44 72 6.1 61 59 6.3no response no response 39 6.0 no response 65 45 6.0 no response 34 <5.573 37 6.2 no response 77 71 7.0 96 6.3 81 72 6.4 77 <5.5 89 85 7.3 noresponse no response 53 6.8 no response 93 83 7.1 no response noresponse 58 6.4 no response % Eff: % Efficacy pEC50: −log EC50 Noresponse: Efficacy < 25% maximum response of carbachol. This level ofactivity is not considered significantly different to no response.

Example 101 Effects of Compound 35AKU-21 on Intaocular Pressure inPrimates.

All studies were conducted in fully conscious female cynomolgus monkeys(Macacca fascicularis) weighing 3–4 kg. Unilateral ocular hypertensionwas produced by argon laser photocoagulation to the mid-trabecularmeshwork (Sawyer & McGuigan, Invest. Ophthalmol. Vis. Sci. 29:81(1988)).

Animals were trained to allow measuring intraocular pressure (IOP) witha model 30 Classic pneumatonometer (Mentor O&O Co.). Throughout eachstudy, monkeys sat in specially designed chairs (Primate Products, SanFrancisco) and fed fruits and juices as needed.

The drug was administered topically. The drug was formulated in anaqueous solution such as distilled water, saline or citrate buffer at apH 5–7 and applied unilaterally as a 35 μL drop; the contralateral eyereceived an equal volume of saline (or vehicle). Two baselinemeasurements were made prior to administration of the drug, followed byperiodic measurements up to 6 hours post drug administration. Theresults of this study are shown below in Table 2.

TABLE 2 Ocular Hypotensive Effect of 35AKU-21 in Glaucomatous MonkeysTIME (HR) 1 2 4 6 % IOP Change −9.3 −21.3 −25.9 −29.2 SEM 2.2 5.0 6.56.2 N 6 6 6 6 p value .008 .009 .016 .012 p value is for comparison tovehicle control in contralateral eye.

1. A compound of formula (I):

wherein: Z₁ is CR₁, Z₂ is CR₂, Z₃ is CR₃, and Z₄ is CR₄; W₁ is S, W₂ isN or CR₆, and W₃ is CG; G is of formula (II):

Y is O, S, CHOH, —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, —(O)CO—, —NR₇—,—CH═N—, or absent; p is 1, 2, 3, 4 or 5; Z is CR₈R₉ or absent; each t is1, 2, or 3; each R₁, R₂, R₃, and R₄, independently, is H, amino,hydroxyl, halo, or straight- or branched-chain C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, methoxymethyl, ethoxymethyl, proproxymethyl, C₁₋₆haloalkyl, —CN, —CF₃, —OR₁₁, —COR₁₁, —NO₂, —SR₁₁, —NHC(O)R₁₁,—C(O)NR₁₂R₁₃, —NR₁₂R₁₃, —NR₁₁C(O)NR₁₂R₁₃, —SO₂NR₁₂R₁₃, —OC(O)R₁₁,—O(CH₂)_(q)NR₁₂R₁₃, or —(CH₂)_(q)NR₁₂R₁₃, where q is an integer from 2to 6, or R₁ and R₂ together form —NH—N═N— or R₃ and R₄ together form—NH—N═N—; each R₅, R₆, and R₇, independently, is H, C₁₋₆ alkyl; formyl;C₃₋₆ cycloalkyl; C₅₋₆ aryl, optionally substituted with halo or C₁₋₆alkyl; or C₅₋₆ heteroaryl, optionally substituted with halo or C₁₋₆alkyl; each R₈ and R₉, independently, is H or straight- orbranched-chain C₁₋₈ alkyl; R₁₀ is straight- or branched-chain C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkylidene, C₁₋₈ alkoxy, ormethoxymethyl, ethoxymethyl, proproxymethyl; R₁₀′ is H, straight- orbranched-chain C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkylidene,C₁₋₈ alkoxy, methoxymethyl, ethoxymethyl, proproxymethyl, C₁₋₈aminoalkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxycarbonyl, C₁₋₈ hydroxyalkoxy,C₁₋₈ hydroxyalkyl, or C₁₋₈ alkylthio; each R₁₁, independently, is H,straight- or branched-chain C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,methoxymethyl, ethoxymethyl, proproxymethyl, C₂₋₈ aminoalkyl, C₂₋₈haloalkyl, C₁₋₈ alkoxycarbonyl, C₂₋₈ hydroxyalkyl, —C(O)—C₅₋₆ arylsubstituted with C₁₋₃ alkyl or halo, C₅₋₆ aryl, C₅₋₆ heteroaryl, C₅₋₆cycloalkyl, C₅₋₆ heterocycloalkyl, —C(O)NR₁₂R₁₃, —CR₅R₁₂R₁₃,—(CH₂)_(t)NR₁₂R₁₃, t is an integer from 2 to 8; and each R₁₂ and R₁₃,independently, is H, C₁₋₆ alkyl; C₃₋₆ cycloalkyl; C₅₋₆ aryl, optionallysubstituted with halo or C₁₋₆ alkyl; or C₅₋₆ heteroaryl, optionallysubstituted with halo or C₁₋₆ alkyl; or a pharmaceutically acceptablesalt, ester or prodrug thereof.
 2. The compound of claim 1, wherein eacht is
 2. 3. The compound of claim 2, wherein R₁₀ is n-butyl.
 4. Thecompound of claim 2, wherein each R₁, R₂, R₃, and R₄, independently, isH, hydroxyl, halo, methoxymethyl, ethoxymethyl, proproxymethyl, CF₃,—NO₂, or straight- or branched-chain C₁₋₆ alkyl, or R₁ and R₂ togetherform —NH—N═N— or R₃ and R₄ together form —NH—N═N—.
 5. The compound ofclaim 2, wherein Y is absent or O, p is 0, 1, 2 or 3, and R₈ and R₉ areH.
 6. The compound of claim 5, wherein Z is absent, Y is absent and p is3.
 7. The compound of claim 6, wherein R₁₀ is n-butyl.
 8. The compoundof claim 1, wherein the compound is: 1-benzo[b]thiophen-2-yl-4-(4-butylpiperidin-1-yl)-butan-1-one4-(4-butylpiperidin-1-yl)-1-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-butan-1-one;1-(3-bromo-benzo[b]thiophen-2-yl)-4-(4-butylpiperidin-1-yl)-butan-1-one1-(3-benzo[b]thiophen-2-yl-propyl)-4-butylpiperidine;4-butyl-1-[3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-propyl]-piperidine;1-(3-benzo[b]thiophen-2-yl-propyl)-4-methylpiperidine1-(3-benzo[b]thiophen-2-yl-propyl)-4-benzylpiperidine; or3-[3-(4-butyl-piperidin-1-yl)-propyl]-benzo[d]isothiazole.
 9. Apharmaceutical composition comprising an effective amount of a compoundof formula (I):

wherein: Z₁ is CR₁, Z₂ is CR₂, Z₃ is CR₃, and Z₄ is CR₄; W₁ is S, W₂ isN or CR₆, and W₃ is CG; G is of formula (II):

Y is O, S, CHOH, —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, —(O)CO—, —NR₇—,—CH═N—, or absent; p is 1, 2, 3, 4 or 5; Z is CR₈R₉ or absent; each t is1, 2, or 3; each R₁, R₂, R₃, and R₄, independently, is H, amino,hydroxyl, halo, or straight- or branched-chain C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, methoxymethyl, ethoxymethyl, proproxymethyl, C₁₋₆haloalkyl, —CN, —CF₃, —OR₁₁, —COR₁₁, —NO₂, —SR₁₁, —NHC(O)R₁₁,—C(O)NR₁₂R₁₃, —NR₁₂R₁₃, —NR₁₁C(O)NR₁₂R₁₃, —SO₂NR₁₂R₁₃, —OC(O)R₁₁,—O(CH₂)_(q)NR₁₂R₁₃, or —(CH₂)_(q)NR₁₂R₁₃, where q is an integer from 2to 6, or R₁ and R₂ together form —NH—N═N— or R₃ and R₄ together form—NH—N═N—; each R₅, R₆, and R₇, independently, is H, C₁₋₆ alkyl; formyl;C₃₋₆ cycloalkyl; C₅₋₆ aryl, optionally substituted with halo or C₁₋₆alkyl; or C₅₋₆ heteroaryl, optionally substituted with halo or C₁₋₆alkyl; each R₈ and R₉, independently, is H or straight- orbranched-chain C₁₋₈ alkyl; R₁₀ is straight- or branched-chain C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkylidene, C₁₋₈ alkoxy, ormethoxymethyl, ethoxymethyl, proproxymethyl; R₁₀′ is H, straight- orbranched-chain C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkylidene,C₁₋₈ alkoxy, methoxymethyl, ethoxymethyl, proproxymethyl, C₁₋₈aminoalkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxycarbonyl, C₁₋₈ hydroxyalkoxy,C₁₋₈ hydroxyalkyl, or C₁₋₈ alkylthio; each R₁₁, independently, is H,straight- or branched-chain C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,methoxymethyl, ethoxymethyl, proproxymethyl, C₂₋₈ aminoalkyl, C₂₋₈haloalkyl, C₁₋₈ alkoxycarbonyl, C₂₋₈ hydroxyalkyl, —C(O)—C₅₋₆ arylsubstituted with C₁₋₃ alkyl or halo, C₅₋₆ aryl, C₅₋₆ heteroaryl, C₅₋₆cycloalkyl, C₅₋₆ heterocycloalkyl, —C(O)NR₁₂R₁₃, —CR₅R₁₂R₁₃,—(CH₂)_(t)NR₁₂R₁₃, t is an integer from 2 to 8; and each R₁₂ and R₁₃,independently, is H, C₁₋₆ alkyl; C₃₋₆ cycloalkyl; C₅₋₆ aryl, optionallysubstituted with halo or C₁₋₆ alkyl; or C₅₋₆ heteroaryl, optionallysubstituted with halo or C₁₋₆ alkyl; or a pharmaceutically acceptablesalt, ester or prodrug thereof.
 10. A pharmaceutical composition ofclaim 9, wherein each t is
 2. 11. A pharmaceutical composition of claim10, wherein R₁₀ is n-butyl.
 12. A pharmaceutical composition of claim10, wherein each R₁, R₂, R₃, and R₄, independently, is H, hydroxyl,halo, methoxymethyl, ethoxymethyl, proproxymethyl, CF₃, —NO₂, orstraight- or branched-chain C₁₋₆ alkyl, or R₁ and R₂ together form—NH—N═N— or R₃ and R₄ together form —NH—N═N—.
 13. A pharmaceuticalcomposition of claim 10, wherein Y is absent or O, p is 0, 1, 2 or 3,and R₈ and R₉ are H.
 14. A pharmaceutical composition of claim 13,wherein Z is absent, Y is absent and p is
 3. 15. A pharmaceuticalcomposition of claim 14, wherein R₁₀ is n-butyl.
 16. A pharmaceuticalcomposition of claim 10, wherein the compound is:1-benzo[b]thiophen-2-yl-4-(4-butylpiperidin-1-yl)-butan-1-one4-(4-butylpiperidin-1-yl)-1-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-butan-1-one;1-(3-bromo-benzo[b]thiophen-2-yl)-4-(4-butylpiperidin-1-yl)-butan-1-one1-(3-benzo[b]thiophen-2-yl-propyl)-4-butylpiperidine;4-butyl-1-[3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-propyl]-piperidine;1-(3-benzo[b]thiophen-2-yl-propyl)-4-methylpiperidine1-(3-benzo[b]thiophen-2-yl-propyl)-4-benzylpiperidine; or3-[3-(4-butyl-piperidin-1-yl)-propyl]-benzo[d]isothiazole.